2021/10/09 更新

写真a

ヒロハタ サトシ
廣畑 聡
HIROHATA Satoshi
所属
保健学域 教授
職名
教授
ホームページ
外部リンク

学位

  • 博士(医学) ( 岡山大学 )

研究キーワード

  • マトリックスメタロプロテアーゼ

  • ADAMTS

  • 細胞外マトリックス

研究分野

  • ライフサイエンス / 生体医工学

  • ライフサイエンス / 循環器内科学

  • その他 / その他  / 病態検査学

  • ライフサイエンス / 生体材料学

  • ライフサイエンス / 整形外科学

  • ライフサイエンス / 病態医化学

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学歴

  • 岡山大学    

    - 1997年

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    国名: 日本国

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  • 岡山大学   Faculty of Medicine  

    - 1992年

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  • 岡山大学   医学部  

    - 1992年

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    国名: 日本国

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経歴

  • - Professor,Graduate School of Health Sciences,Okayama University

    2014年

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  • - 岡山大学保健学研究科 教授

    2014年

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  • 岡山大学グローバル・パートナーズ 准教授   Center for Global Partnerships and Education

    2012年 - 2014年

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  • Associate Professor,Center for Global Partnerships and Education,Okayama University

    2012年 - 2014年

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  • 岡山大学医歯薬学総合研究科 助教

    2004年 - 2012年

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  • Assistant Professor,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama University

    2004年 - 2012年

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  • postdoctoral fellow,Cleveland Clinic Foundation Lerner Research Institute

    1997年 - 2000年

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  • クリーブランドクリニック ラーナー研究所 博士研究員

    1997年 - 2000年

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所属学協会

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委員歴

  • 日本動脈硬化学会   専門医  

    2014年7月 - 現在   

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    団体区分:学協会

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  • 日本循環器学会   演題査読員  

    2007年 - 2017年   

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    団体区分:学協会

    日本循環器学会

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  • 日本循環器学会   専門医  

    2004年4月 - 現在   

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    団体区分:学協会

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  • 日本結合組織学会   評議員  

    2002年   

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    団体区分:学協会

    日本結合組織学会

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  • 日本内科学会   総合内科専門医  

    2000年   

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    団体区分:学協会

    日本内科学会

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論文

  • Osteopontin silencing attenuates bleomycin-induced murine pulmonary fibrosis by regulating epithelial–mesenchymal transition 査読

    Omer Faruk Hatipoglu, Eyyup Uctepe, Gabriel Opoku, Hidenori Wake, Kentaro Ikemura, Takashi Ohtsuki, Junko Inagaki, Mehmet Gunduz, Esra Gunduz, Shogo Watanabe, Takashi Nishinaka, Hideo Takahashi, Satoshi Hirohata

    Biomedicine & Pharmacotherapy   139   111633 - 111633   2021年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.biopha.2021.111633

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  • Induction of CEMIP in Chondrocytes by Inflammatory Cytokines: Underlying Mechanisms and Potential Involvement in Osteoarthritis. 査読 国際誌

    Takashi Ohtsuki, Omer F Hatipoglu, Keiichi Asano, Junko Inagaki, Keiichiro Nishida, Satoshi Hirohata

    International journal of molecular sciences   21 ( 9 )   2020年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:MDPI  

    In patients with osteoarthritis (OA), there is a decrease in both the concentration and molecular size of hyaluronan (HA) in the synovial fluid and cartilage. Cell migration-inducing hyaluronidase 1 (CEMIP), also known as hyaluronan (HA)-binding protein involved in HA depolymerization (HYBID), was recently reported as an HA depolymerization-related molecule expressed in the cartilage of patients with OA. However, the underlying mechanism of CEMIP regulation is not well understood. We found that CEMIP expression was transiently increased by interleukine-1β (IL-1β) stimulation in chondrocytic cells. We also observed that ERK activation and NF-κB nuclear translocation were involved in the induction of CEMIP by IL-1β. In addition, both administration of HA and mechanical strain attenuated the CEMIP induction in IL-1β-stimulated chondrocytes. In conclusion, we clarified the regulatory mechanism of CEMIP in chondrocytes by inflammatory cytokines and suggested the potential involvement in osteoarthritis development.

    DOI: 10.3390/ijms21093140

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  • Connective tissue growth factor induction in a pressure-overloaded heart ameliorated by the angiotensin II type 1 receptor blocker olmesartan 査読 国際誌

    Mutsumi Iwamoto, Satoshi Hirohata, Hiroko Ogawa, Takashi Ohtsuki, Ryoko Shinohata, Toru Miyoshi, O. Faruk Hatipoglu, Shozo Kusachi, Kazuhide Yamamoto, Yoshifumi Ninomiya

    HYPERTENSION RESEARCH   33 ( 12 )   1305 - 1311   2010年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Connective tissue growth factor (CTGF) is a secreted protein that regulates fibrosis. We hypothesized that CTGF is induced in a pressure-overloaded (PO) heart and that blocking the angiotensin II type 1 receptor would reduce CTGF expression. Accordingly, we administered olmesartan and compared its effects with other antihypertensive drugs in a PO heart. CTGF induction was determined in a rat PO model, and olmesartan, hydralazine or saline was continuously administered. The effects of olmesartan on CTGF induction, myocyte hypertrophy and fibrosis were evaluated. The effect of olmesartan on cardiac function was also examined in CTGF-and transforming growth factor-beta 1 (TGF-beta 1)-infused rats. CTGF was increased in the PO heart 3 days after aortic banding and was markedly distributed around the perivascular fibrotic area. After 28 days, blood pressure was not significantly different in the olmesartan and hydralazine groups, but olmesartan treatment reduced CTGF distribution in PO hearts. Olmesartan was associated with a significantly reduced myocyte hypertrophy index (4.77 +/- 0.48 for olmesartan and 6.05 +/- 1.45 for saline, P<0.01), fibrosis area (32.0 +/- 15.5% compared with the saline group, P<0.05) and serum TGF-beta 1 level (62.6 +/- 10.6 ng ml(-1) for olmesartan and 84.4 +/- 7.2 ng ml(-1) for hydralazine, P<0.05). In addition, cardiac function was significantly preserved in the olmesartan group compared with the saline group. Finally, olmesartan ameliorated the cardiac dysfunction in CTGF-and TGF-beta 1-infused rats. Olmesartan attenuated CTGF induction, reduced perivascular fibrosis and ameliorated cardiac dysfunction in a PO heart. Our results provide insight into the beneficial effects of olmesartan on PO hearts, independent of blood-pressure lowering. Hypertension Research (2010) 33, 1305-1311; doi:10.1038/hr.2010.189; published online 14 October 2010

    DOI: 10.1038/hr.2010.189

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  • Plasma Arginase-1 Level Is Associated with the Mental Status of Outpatients with Chronic Liver Disease 査読 国際誌

    Noriyoshi Ogino, Fusao Ikeda, Shihoko Namba, Shinnosuke Ohkubo, Tomoaki Nishimura, Hiroyuki Okada, Satoshi Hirohata, Narufumi Suganuma, Keiki Ogino

    DIAGNOSTICS   11 ( 2 )   2021年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:MDPI  

    While plasma arginase-1 has been suggested as a biomarker of mental status in healthy individuals, it has not been evaluated in patients with chronic liver disease. This cross-sectional study investigated the utility of plasma arginase-1 for screening mental status in patients with chronic liver disease. This study included outpatients with chronic liver disease who underwent regular check-ups at Okayama University Hospital between September 2018 and January 2019. In addition to the standard blood tests, the plasma arginase-1 level was analyzed. The patients' mental status was assessed using the Japanese version of the General Health Questionnaire-28 (GHQ-28). The associations between mental status and various parameters, including plasma arginase-1, were investigated using logistic regression analysis. Among 114 participating patients, 8 were excluded, comprising 6 with insufficient blood samples for plasma arginase-1 measurement and 2 with incomplete questionnaires. Multivariate binomial logistic regression analysis revealed that plasma arginase-1 was significantly and negatively associated with the GHQ-total score, especially somatic symptoms. Therefore, plasma arginase-1 may be a useful biomarker for assessing the mental status of outpatients with chronic liver disease.

    DOI: 10.3390/diagnostics11020317

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  • Low plasma apolipoprotein E-rich high-density lipoprotein levels in patients with metabolic syndrome 査読 国際誌

    Ryoko Shinohata, Yuhei Shiga, Shin-ichiro Miura, Satoshi Hirohata, Misako Shibakura, Tomoe Ueno-Iio, Shogo Watanabe, Yujiro Arao, Shinichi Usui

    CLINICA CHIMICA ACTA   510   531 - 536   2020年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER  

    Background: High-density lipoprotein (HDL) containing apolipoprotein E (apoE-rich HDL) represents a small portion of plasma HDL. We recently established a method for measuring plasma apoE-rich HDL. This study aimed to investigate the relationship between metabolic syndrome (MetS) and apoE-rich HDL levels.Methods: The apoE-rich HDL-cholesterol (HDL-C) levels and metabolic characteristics of 113 patients were analyzed.Results: The MetS group (n = 58) had significantly lower apoE-rich HDL-C and a lower apoE-rich HDL-C/HDL-C ratio (apoE-HDL (%)) compared to the non-MetS group. The prevalence of MetS was increased when apoE-HDL (%) decreased. In simple regression analyses, apoE-HDL (%) was significantly inversely correlated with visceral fat area (r(s) = - 0.370, P < 0.001) and plasma triglycerides (r(s) = - 0.447, P < 0.001) and positively correlated with low-density lipoprotein (LDL) mean particle size (r(s) = 0.599, P < 0.001) and HDL mean particle size (r(s) = 0.512, P < 0.001). Stepwise multiple regression analysis revealed that LDL mean particle size, a component of the atherogenic lipoprotein profile, was an independent predictor of apoE-HDL (%) (adjusted R-2 = 0.409).Conclusions: Plasma apoE-rich HDL levels might be a valuable indicator of MetS. These findings may help further understand HDL subfraction analysis in cardiometabolic diseases.

    DOI: 10.1016/j.cca.2020.08.020

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  • Efficacy of an Adjunctive Electrophysiological Test–Guided Left Atrial Posterior Wall Isolation in Persistent Atrial Fibrillation Without a Left Atrial Low-Voltage Area 査読

    Hirosuke Yamaji, Shunichi Higashiya, Takashi Murakami, Kazuyoshi Hina, Hiroshi Kawamura, Masaaki Murakami, Shigeshi Kamikawa, Satoshi Hirohata, Shozo Kusachi

    Circulation: Arrhythmia and Electrophysiology   13 ( 8 )   2020年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Ovid Technologies (Wolters Kluwer Health)  

    <sec>
    <title>Background:</title>
    Electrical remodeling precedes structural remodeling. In adjunctive left atrial (LA) low-voltage area (LVA) ablation to pulmonary vein isolation of atrial fibrillation (AF), LA areas without LVA have not been targeted for ablation. We studied the effect of adjunctive LA posterior wall isolation (PWI) on persistent AF without LA-LVA according to electrophysiological testing (EP test).


    </sec>
    <sec>
    <title>Methods:</title>
    We examined consecutive patients with persistent AF with (n=33) and without (n=111) LA-LVA. Patients without LA-LVA were randomly assigned to EP test–guided (n=57) and control (n=54) groups. In the EP test–guided group, an adjunctive PWI was performed in those with positive results (PWI subgroup; n=24), but not in those with negative results (n=33). The criteria for positive EP tests were an effective refractory period ≤180 ms, effective refractory period&gt;20 ms shorter than the other sites, and/or induction of AF/atrial tachycardia (AT) during measurements. LVA ablation was performed in the patients with LA-LVA.


    </sec>
    <sec>
    <title>Results:</title>

    During the follow-up period (62±33 weeks), the EP test–guided group had significantly lower recurrence rates (19%,11/57 versus 41%, 22/54,
    <italic>P</italic>
    =0.012) and higher Kaplan-Meier AF/AT–free survival curve rates than the control group (
    <italic>P</italic>
    =0.01). No significant differences in the recurrence and AF/AT–free survival curve rates between the PWI (positive EP test) and non-PWI (negative EP test) subgroups were observed. Therefore, PWI for positive EP tests reduced the AF/AT recurrence in the EP test–guided group. A stepwise Cox proportional hazard analyses identified EP test–guided ablation as a factor reducing the recurrence rate. The recurrence rates in the LA-LVA ablation group and EP test–guided group were similar.



    </sec>
    <sec>
    <title>Conclusions:</title>
    This pilot study proposed that an EP test–guided adjunctive PWI of persistent AF without LA-LVA potentially reduced AF/AT recurrences. The results suggest that there is an AF substrate in the LA with altered electrophysiological function even when there is no LA-LVA.


    </sec>
    <sec>
    <title>Graphic Abstract:</title>

    A
    <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="graphic abstract">graphic abstract</ext-link>
    is available for this article.



    </sec>

    DOI: 10.1161/circep.119.008191

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  • Bile acids aggravate nonalcoholic steatohepatitis and cardiovascular disease in SHRSP5/Dmcr rat model 査読

    Shusei Yamamoto, Ikumi Sato, Natsuki Fukuhama, Natsumi Akiyama, Miku Sakai, Shota Kumazaki, Shang Ran, Satoshi Hirohata, Kazuya Kitamori, Yukio Yamori, Shogo Watanabe

    Experimental and Molecular Pathology   114   104437 - 104437   2020年6月

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  • Deficiency of CD44 prevents thoracic aortic dissection in a murine model. 査読 国際誌

    Omer F Hatipoglu, Toru Miyoshi, Tomoko Yonezawa, Megumi Kondo, Naofumi Amioka, Masashi Yoshida, Satoshi Akagi, Kazufumi Nakamura, Satoshi Hirohata, Hiroshi Ito

    Scientific reports   10 ( 1 )   6869 - 6869   2020年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Thoracic aortic dissection (TAD) is a life-threatening vascular disease. We showed that CD44, a widely distributed cell surface adhesion molecule, has an important role in inflammation. In this study, we examined the role of CD44 in the development of TAD. TAD was induced by the continuous infusion of β-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, and angiotensin II (AngII) for 7 days in wild type (WT) mice and CD44 deficient (CD44-/-) mice. The incidence of TAD in CD44-/- mice was significantly reduced compared with WT mice (44% and 6%, p < 0.01). Next, to evaluate the initial changes, aortic tissues at 24 hours after BAPN/AngII infusion were examined. Neutrophil accumulation into thoracic aortic adventitia in CD44-/- mice was significantly decreased compared with that in WT mice (5.7 ± 0.3% and 1.6 ± 0.4%, p < 0.01). In addition, BAPN/AngII induced interleukin-6, interleukin-1β, matrix metalloproteinase-2 and matrix metalloproteinase-9 in WT mice, all of which were significantly reduced in CD44-/- mice (all p < 0.01). In vitro transmigration of neutrophils from CD44-/- mice through an endothelial monolayer was significantly decreased by 18% compared with WT mice (p < 0.01). Our findings indicate that CD44 has a critical role in TAD development in association with neutrophil infiltration into adventitia.

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  • Activated clotting time on the day of atrial fibrillation ablation for minimally interrupted and uninterrupted direct oral anticoagulation therapy: Sequential changes, differences among direct oral anticoagulants, and ablation safety outcomes 国際誌

    Hirosuke Yamaji, Takashi Murakami, Kazuyoshi Hina, Shunich Higashiya, Hiroshi Kawamura, Masaaki Murakami, Shigeshi Kamikawa, Satoshi Hirohata, Shozo Kusachi

    JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY   30 ( 12 )   2823 - 2833   2019年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Background Activated clotting time (ACT)-guided heparinization is used during atrial fibrillation (AF) ablation. Differences in sensitivity to ACT assays have been identified among different direct oral anticoagulants (DOACs). Objective We aimed to examine ACT just before ablation (pre-ACT) for different ablation start times (9:00, 11:00, 13:00, or 15:00) and ablation safety outcomes in minimally interrupted (min-Int) and uninterrupted (Unint) DOAC regimens and examine differences in pre-ACT values among four DOACs. Methods Consecutive patients were randomized into the min-Int (n = 307) or Unint (n = 277) groups. DOACs examined were apixaban, dabigatran, edoxaban, and rivaroxaban. Results No sequential changes in pre-ACT values were observed for each DOAC used and for all four DOACs combined in the min-Int and Unint groups. There was no meaningful difference in pre-ACT at each ablation start time between the groups. Clinically significant differences in overall pre-ACT were not obtained between the groups (138 +/- 24 vs 142 +/- 23 seconds). The pre-ACT (baseline) value for dabigatran was on average 29 seconds higher than that for the other three DOACs. The min-Int and Unint groups showed similar thromboembolic (0% vs 0%) and bleeding event rates (major, 1% vs 0%; all, 3.5% vs 2.5%). Conclusion The pre-ACT did not show a sequential change in the min-Int and Unint groups. No notable differences in the time-dependent change in pre-ACT between the groups were observed. Variations in baseline ACT suggest the need for moderate adjustment of ACT for adequate modification of heparin dose for the other three DOACs. Both regimens provided similar acceptable AF ablation safety outcomes.

    DOI: 10.1111/jce.14260

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  • Mechanical strain attenuates cytokine-induced ADAMTS9 expression via transient receptor potential vanilloid type 1. 査読 国際誌

    Ohtsuki T, Shinaoka A, Kumagishi-Shinaoka K, Asano K, Hatipoglu OF, Inagaki J, Takahashi K, Oohashi T, Nishida K, Naruse K, Hirohata S

    Experimental cell research   383 ( 2 )   111556 - 111556   2019年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Effects of Oral Anticoagulants on Patients With Atrial Fibrillation Aged 90 Years and Older: Comparison Among Direct Oral Anticoagulant, Warfarin Anticoagulant, and Nonanticoagulation 国際誌

    Hirosuke Yamaji, Shunichi Higashiya, Takashi Murakami, Kazuyoshi Hina, Hiroshi Kawamura, Masaaki Murakami, Shigeshi Kamikawa, Satoshi Hirohata, Shozo Kusachi

    JOURNAL OF CARDIOVASCULAR PHARMACOLOGY   74 ( 3 )   246 - 254   2019年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    This study aimed to investigate the effects of anticoagulants on ultra-aged patients with nonvalvular atrial fibrillation (AF). We retrospectively studied 320 consecutive patients with AF (median age, 91 years; range 90-100.1 years). Patients were categorized as follows: patients taking direct oral anticoagulant (DOAC group, n = 93), those taking warfarin (warfarin group, n = 147), and those not taking oral anticoagulants (non-OAC group, n = 80). During the follow-up periods (median 3.00 years; first and fourth quantiles, 1.13 and 4.56 years, respectively), in thromboembolic events, the DOAC, warfarin, and non-OAC groups showed the lowest (0%, 0/93; 0%/year), intermediate (4.7%, 7/149; 1.43%/year), and highest (5%, 4/80; 2.65%/year) incidence rates, respectively. In major bleeding events, the DOAC, warfarin, and non-OAC groups showed the highest (9.67%, 9/96; 5.00%/year), intermediate (8.1%, 12/149; 2.46%/year), and lowest (0%, 0/80; 0%/year) incidence rates, respectively. These differences in the relationships of the 3 groups were statistically significant. Confounding factors did not affect these results. Bruises associated with impairment of motor function with aging caused major bleeding in approximately 60% of major bleeding cases. The Cox proportional hazards model revealed that warfarin decreased mortality, whereas antiplatelet drugs increased mortality. In conclusion, DOACs had considerably high incidence of major bleeding events, whereas absence of OAC treatment was associated with substantially high thromboembolic events. Warfarin showed acceptable incidence ratios of both events. At present, warfarin is thus believed to be adequate for ultra-aged ($90 years) patients with nonvalvular AF. Avoidance of bruises was important to prevent major bleeding events. Antiplatelet drugs were suggested not to be adequate for these patients.

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  • Serum malondialdehyde-modified low-density lipoprotein levels on admission predict prognosis in patients with acute coronary syndrome undergoing percutaneous coronary intervention 国際誌

    Naofumi Amioka, Toru Miyoshi, Hiroaki Otsuka, Daisuke Yamada, Atsushi Takaishi, Masayuki Ueeda, Satoshi Hirohata, Hiroshi Ito

    JOURNAL OF CARDIOLOGY   74 ( 3-4 )   258 - 266   2019年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER  

    Background: Malondialdehyde-modified low-density lipoprotein (MDA-LDL) is a predictive marker of cardiovascular events in patients with stable angina pectoris. However, little is known about this marker in patients with acute coronary syndrome (ACS). We investigated the prognostic relevance of MDA-LDL to cardiovascular outcomes in patients with ACS.Methods: A total of 370 consecutive patients with ACS who underwent primary percutaneous coronary intervention (PCI) were enrolled from October 2009 to September 2014 at Mitoyo General Hospital. Serum MDA-LDL levels were measured at admission. The patients were divided into three tertile groups according to serum MDA-LDL levels. The primary outcomes were cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, revascularization, and heart failure requiring hospital admission.Results: MDA-LDL levels in patients with acute myocardial infarction were significantly greater than those in patients with unstable angina pectoris (mean +/- standard deviation: 133 +/- 48 U/L vs.157 +/- 69 U/L, p = 0.001). During follow-up [472 (195-920) days], 82 (22%) events occurred. Kaplan-Meier analysis showed that patients in the highest MDA-LDL tertile had the worst prognosis (log-rank, p < 0.001). Cox regression analysis showed that serum MDA-LDL levels were an independent predictor of cardiovascular events after PCI in patients with ACS, even after adjustment for age, sex, body mass index, conventional cardiovascular risk factors, other lipid biomarkers, statin use on admission, cardiac biomarkers, and presence or absence of multivessel disease (hazard ratio: 1.80 per 1 standard deviation U/L increase, 95% confidence interval: 1.07-3.16, p = 0.027).Conclusion: Serum MDA-LDL levels on admission are a significant prognostic marker in patients with ACS who undergo successful PCI. (C) 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.jjcc.2019.02.012

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  • BMPR2変異を伴うPAHにおけるSMCのエピジェネティックな変化に対する低酸素の重要な役割(Crucial Role of Hypoxia in Epigenetic Changes of SMCs from PAH with BMPR2 Mutation) 査読

    中村 一文, 赤木 達, 斎藤 幸弘, 江尻 健太郎, 三好 亨, 吉田 賢司, 廣畑 聡, 伊藤 浩

    日本循環器学会学術集会抄録集   83回   OJ10 - 3   2019年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • Non-alcoholic steatohepatitis aggravates nitric oxide synthase inhibition-induced arteriosclerosis in SHRSP5/Dmcr rat model 国際誌

    Shogo Watanabe, Shota Kumazaki, Shusei Yamamoto, Ikumi Sato, Kazuya Kitamori, Mari Mori, Yukio Yamori, Satoshi Hirohata

    INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY   99 ( 6 )   282 - 294   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Non-alcoholic steatohepatitis (NASH) is linked to increased cardiovascular risk, independent of the broad spectrum of metabolic syndrome risk factors. Stroke-prone (SP) spontaneously hypertensive rats (SHRSP5/Dmcr) fed a high-fat and high-cholesterol (HFC) diet developed hepatic lesions similar to those in human NASH pathology. These rats simultaneously developed lipid deposits in the mesenteric arteries, cardiac fibrosis, endothelial dysfunction and left ventricle (LV) diastolic dysfunction. However, the intermediary factors between NASH and cardiovascular disease are still unknown. We investigated whether NASH aggravates nitric oxide (NO) synthase inhibition-induced arteriosclerosis in SHRSP5/Dmcr rats. Wistar Kyoto and SHRSP5/Dmcr rats were divided into 4 groups of 5 and fed the stroke-prone (SP) or HFC diets for 8 weeks. To induce NO synthase inhibition, N-omega-nitro-L-arginine methyl ester hydrochloride (L-NAME) mixed with drinking water was administered in the final 2 weeks. The NASH+ L-NAME group demonstrated the following characteristics related to arteriosclerosis and myocardial ischaemia: (a) LV systolic dysfunction with asynergy, (b) replacement fibrosis caused by the shedding of cardiomyocytes and (c) arterial lipid deposition and coronary occlusion secondary to endothelial dysfunction. These characteristics were not observed in the NASH or non-NASH+ L-NAME groups. The SHRSP5/Dmcr rat model demonstrates that NASH significantly aggravates cardiovascular risk.

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  • Impact of Serum Malondialdehyde-Modified Low-Density Lipoprotein Levels on Admission for Predicting Prognosis in Patients With Acute Coronary Syndrome Who Received Successful Percutaneous Coronary Intervention.

    Naofumi Amioka, Toru Miyoshi, Hiroaki Otsuka, Atsushi Takaishi, Masayuki Ueeda, Satoshi Hirohata, Hiroshi Ito

    CIRCULATION   138   2018年11月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • High molecular weight hyaluronan protects cartilage from degradation by inhibiting aggrecanase expression. 査読

    Ohtsuki T, Asano K, Inagaki J, Shinaoka A, Kumagishi-Shinaoka K, Cilek MZ, Hatipoglu OF, Oohashi T, Nishida K, Komatsubara I, Hirohata S

    J Orthop Res.   1 - 9   2018年8月

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  • A rapid and precise method for measuring plasma apoE-rich HDL using polyethylene glycol and cation-exchange chromatography: a pilot study on the clinical significance of apoE-rich HDL measurements 査読 国際誌

    Toru Ikeda, Ryoko Shinohata, Masaaki Murakami, Kazuyoshi Hina, Shigeshi Kamikawa, Satoshi Hirohata, Shozo Kusachi, Arisa Tamura, Shinichi Usui

    CLINICA CHIMICA ACTA   465   112 - 118   2017年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Background: High-density lipoprotein (HDL) containing apolipoprotein E (apoE-rich HDL) represents only a small portion of plasma HDL. Reliable methods for determining and isolating apoE-rich HDL have not been well studied.
    Methods: We established a novel analytical method for apoE-rich HDL using polyethylene glycol and a cation-exchange column (PEG-column method). Furthermore, we examined biochemical correlates of apoE-rich HDL-cholesterol (HDL-C) in 36 patients who underwent coronary computed tomographic angiography.
    Results: Our PEG-column method demonstrated high reproducibility (coefficient of variation &lt;3.52%) and linearity up to 15 mg/dl for apoE-rich HDL-C concentrations. Isolated apoE-rich HDL exhibited a larger diameter (14.8 nm) than apoE-poor HDL (10.8 nm) and contained both apoE and apoA-I. ApoE-rich HDL-C concentrations correlated significantly with triglycerides (r(s) = -0.646), LDL size (r(s) = 0.472), adiponectin (r(s) = 0.476), and other lipoprotein components. No significant correlation was obtained with the coronary calcium score. Multiple regression analysis revealed that plasma triglycerides and adiponectin concentrations remained significant independent predictors of apoE-rich (adjusted R-2 = 0.486) but not apoE-poor HDL-C.
    Conclusions: The PEG-column method demonstrated, to various degrees, significant correlations between HDL subtractions and several lipid-related biomarkers involved in an atherogenic lipoprotein profile. Our separation technique for apoE-rich HDL is useful to clarify the role of apoE-rich HDL in atherosclerosis. (C) 2016 Elsevier B.V. All rights reserved.

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  • MMP-13 is constitutively produced in human chondrocytes and co-endocytosed with ADAMTS-5 and TIMP-3 by the endocytic receptor LRP1 査読 国際誌

    Kazuhiro Yamamoto, Hiroshi Okano, Wakako Miyagawa, Robert Visse, Yasuyuki Shitomi, Salvatore Santamaria, Jayesh Dudhia, Linda Troeberg, Dudley K. Strickland, Satoshi Hirohata, Hideaki Nagase

    MATRIX BIOLOGY   56   57 - 73   2016年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Matrix metalloproteinase 13 (MMP-13) degrades collagenous extracellular matrix and its aberrant activity associates with diseases such as arthritis, cancer, atherosclerosis and fibrosis. The wide range of MMP-13 proteolytic capacity suggests that it is a powerful, potentially destructive proteinase and thus it has been believed that MMP-13 is not produced in most adult human tissues in the steady state. Present study has revealed that human chondrocytes isolated from healthy adults constitutively express and secrete MMP-13, but that it is rapidly endocytosed and degraded by chondrocytes. Both pro- and activated MMP-13 bind to clusters II and III of low-density lipoprotein (LDL) receptor-related protein 1 (LRP1). Domain deletion studies indicated that the hemopexin domain is responsible for this interaction. Binding competition between MMP-13 and ADAMTS-4,-5 or TIMP-3, which also bind to cluster II, further shown that the MMP-13 binding site within cluster II is different from those of ADAMTS-4,-5 or TIMP-3. MMP-13 is therefore co-endocytosed with ADAMTS-5 and TIMP-3 by human chondrocytes. These findings indicate that MMP-13 may play a role on physiological turnover of cartilage extracellular matrix and that LRP1 is a key modulator of extracellular levels of MMP-13 and its internalization is independent of the levels of ADAMTS-4,-5 and TIMP-3. (C) 2016 The Authors. Published by Elsevier B.V.

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  • Subclavian steal syndrome: A case report and review of advances in diagnostic and treatment approaches 査読

    Issei Komatsubara, Jun Kondo, Maki Akiyama, Hidemi Takeuchi, Kunio Nogami, Shinichi Usui, Satoshi Hirohata, Shozo Kusachi

    Cardiovascular Revascularization Medicine   17 ( 1 )   54 - 58   2016年1月

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    記述言語:英語   出版者・発行元:Elsevier Inc.  

    Using recently developed diagnostic and treatment methods, we successfully diagnosed and treated a case of subclavian steal syndrome. Syncope and left upper arm weakness suggested ischemia of the cerebral and left upper arm circulation. Volume-plethysmographic blood pressure measurements clarified the differences between the upper arms simultaneously. A high-resolution Doppler instrument revealed a retrograde left vertebral artery waveform, indicating subclavian steal syndrome. Aortography demonstrated proximal left subclavian artery occlusion. The patient was treated with stent implantation via a femoral approach using the latest equipment. Advances in diagnostic and treatment approaches for this syndrome are reviewed in connection with this case.Summary: We present a case of subclavian steal syndrome successfully diagnosed using the latest technology and treated with stent implantation. The syndrome and its treatment are reviewed.

    DOI: 10.1016/j.carrev.2015.11.001

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  • Interleukin-1β induced nuclear factor-κB binds to a disintegrin-like and metalloproteinase with thrombospondin type 1 motif 9 promoter in human chondrosarcoma cells. 査読 国際誌

    Altuntas A, Halacli SO, Cakmak O, Erden G, Akyol S, Ugurcu V, Hirohata S, Demircan K

    Molecular medicine reports   12 ( 1 )   595 - 600   2015年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3892/mmr.2015.3444

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  • Early eicosapentaenoic acid treatment after percutaneous coronary intervention reduces acute inflammatory responses and ventricular arrhythmias in patients with acute myocardial infarction: A randomized, controlled study 査読 国際誌

    Masayuki Doi, Kazumasa Nosaka, Toru Miyoshi, Mutsumi Iwamoto, Masahito Kajiya, Keisuke Okawa, Rie Nakayama, Wataru Takagi, Ko Takeda, Satoshi Hirohata, Hiroshi Ito

    INTERNATIONAL JOURNAL OF CARDIOLOGY   176 ( 3 )   577 - 582   2014年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    Objective: We examined whether early loading of eicosapenlaenoic acid (EPA) reduces clinical adverse events by 1 month, accompanied by a decrease in C-reactive protein (CRP) values in patients with acute myocardial infarction (MI).
    Background: Acute MI triggers an inflammatory reaction, which plays an important role in myocardial injury. EPA could attenuate the inflammatory response.
    Methods: This prospective, open-label, blinded endpoint, randomized trial consisted of 115 patients with acute MI. They were randomly assigned to the EPA group (57 patients) and the control group (58 patients). After percutaneous coronary intervention (PCI), 1800 mg/day of EPA was initiated within 24 h.The primary endpoint was composite events, including cardiac death, stroke, re-infarction, ventricular arrhythmias, and paroxysmal atrial fibrillation within 1 month.
    Results: Administration of EPA significantly reduced the primary endpoint within 1 month (10.5 vs 29.3%, p = 0.01), especially the incidence of ventricular arrhythmias (7.0 vs 20.6%, p = 0.03). Peak CRP values after PCI in the EPA group were significantly lower than those in the control group (median [interquartile range], 8.2 [5.6-10.21 mg/dl vs 9.7 [7.6-13.91 mg/dl p &lt; 0.01). Logistic regression analysis showed that EPA use was an independent factor related to ventricular arrhythmia until 1 month, with an odds ratio of 0.29 (95% confidence interval, 0.09 to 0.96, p = 0.04).
    Conclusions: Early EPA treatment after PCI in the acute stage of MI reduces the incidence of ventricular arrhythmias, and lowers CRP values. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

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  • ADAMTS1 inhibits lymphangiogenesis by attenuating phosphorylation of the lymphatic endothelial cell-specific VEGF receptor. 査読 国際誌

    Junko Inagaki, Katsuyuki Takahashi, Hiroko Ogawa, Keiichi Asano, Omer Faruk Hatipoglu, Mehmet Zeynel Cilek, Masanari Obika, Takashi Ohtsuki, Matthias Hofmann, Shozo Kusachi, Yoshifumi Ninomiya, Satoshi Hirohata

    Experimental cell research   323 ( 2 )   263 - 75   2014年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Angiogenesis and lymphangiogenesis play roles in malignant tumor progression, dissemination, and metastasis. ADAMTS1, a member of the matrix metalloproteinase family, is known to inhibit angiogenesis. Recombinant ADAMTS1 was shown to strongly inhibit angiogenesis. We investigated whether ADAMTS1 inhibited lymphangiogenesis in the present study. We examined cell proliferation and cell migration in normal human dermal lymphatic microvascular endothelial cells (HMVEC-dLy) transduced with or without adenoviral human ADAMTS1 gene therapy. We then examined the VEGFC/VEGFR3 signal transduction pathway in ADAMTS1-transduced HMVEC-dLy. Cell proliferation and tube formation in Matrigel were significantly lower with transduced ADAMTS1 than with control (non-transduced HMVEC-dLy). The phosphorylation of VEGFR3 was also attenuated by ADAMTS1 gene therapy in HMVEC-dLy. Immunoprecipitation assays revealed that ADAMTS1 formed a complex with VEGFC. Our results demonstrated that ADAMTS1 inhibited lymphangiogenesis in vitro. The data highlight the new function of ADAMTS1 in the regulation of lymphangiogenesis and the therapeutic potential of ADAMTS1 in cancer therapy.

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  • Low serum level of secreted frizzled-related protein 5, an anti-inflammatory adipokine, is associated with coronary artery disease 査読 国際誌

    Toru Miyoshi, Masayuki Doi, Shinichi Usui, Mutsumi Iwamoto, Masahito Kajiya, Ko Takeda, Kazumasa Nosaka, Rie Nakayama, Keisuke Okawa, Wataru Takagi, Kazufumi Nakamura, Satoshi Hirohata, Hiroshi Ito

    ATHEROSCLEROSIS   233 ( 2 )   454 - 459   2014年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    Objective: Secreted frizzled-related protein 5 (SFRP5) is an anti-inflammatory adipokine that is associated with insulin resistance in animals. To extend these observations to humans, we investigated the association of serum SFRP5 levels in subjects with and without coronary artery disease (CAD).
    Methods: Subjects (n = 185, 68 + 11 years, 79% male) suspected of having CAD were enrolled in the study and were divided into two groups, CAD and non-CAD subjects, according to the results of their coronary angiographies. Serum SFRP5 levels of the subjects were measured by an enzyme-linked immunosorbent assay.
    Results: The serum SFRP5 levels in the subjects with CAD were significantly lower than those in the non-CAD subjects (median [interquartile range]: 47.7 [26.6] vs. 52.4 [29.6] ng/mL, respectively; p = 0.02). The serum SFRP5 levels significantly correlated with body mass index, the homeostasis model of assessment of insulin resistance, adiponectin levels, and CAD severity. Multivariate logistic regression analysis revealed that a decreased serum SFRP5 level (log transformed) was independently associated with CAD for all subjects (adjusted odds ratio, 0.36; 95% confidence interval, 0.14-0.94; p = 0.03).
    Conclusion: Serum SFRP5 levels are significantly associated with CAD in humans, suggesting that low SFRP5 levels may contribute to CAD. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

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  • Vascular endothelial growth factor C-induced lymphangiogenesis decreases tumor interstitial fluid pressure and tumor. 国際誌

    Matthias Hofmann, Ralph Pflanzer, Nadja Nicole Zoller, August Bernd, Roland Kaufmann, Diamant Thaci, Jurgen Bereiter-Hahn, Satoshi Hirohata, Stefan Kippenberger

    Translational oncology   6 ( 4 )   398 - 404   2013年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Characteristically, most solid tumors exhibit an increased tumor interstitial fluid pressure (TIFP) that directly contributes to the lowered uptake of macromolecular therapeutics into the tumor interstitium. Abnormalities in the tumor-associated lymph vessels are a central brick in the development and prolonged sustaining of an increased TIFP. In the current study, vascular endothelial growth factor C (VEGF-C) was used to enhance tumor-associated lymphangiogenesis as a new mechanism to actively reduce the TIFP by increased lymphatic drainage of the tumor tissue. Human A431 epidermoid vulva carcinoma cells were inoculated in NMRI nu/nu mice to generate a xenograft mouse model. Seven days after tumor cell injection, VEGF-C was peritumorally injected to induce lymphangiogenesis. Tumor growth and TIFP was lowered significantly over time in VEGF-C-treated tumors in comparison to control or VEGF-A-treated animals. These data demonstrate for the first time that actively induced lymphangiogenesis can lower the TIFP in a xenograft tumor model and apparently reduce tumor growth. This model represents a novel approach to modulate biomechanical properties of the tumor interstitium enabling a lowering of TIFP in vivo.

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  • ADAMTS1, ADAMTS5, ADAMTS9 and aggrecanase-generated proteoglycan fragments are induced following spinal cord injury in mouse 査読 国際誌

    Kadir Demircan, Tomoko Yonezawa, Tomoyuki Takigawa, Vehap Topcu, Serpil Erdogan, Fatma Ucar, Ferah Armutcu, M. Ramazan Yigitoglu, Yoshifumi Ninomiya, Satoshi Hirohata

    NEUROSCIENCE LETTERS   544   25 - 30   2013年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) proteinases are involved in a variety of biological processes such as angiogenesis, cancer and arthritis. ADAMTSs appears to be responsible for the cleavage of proteoglycans in several tissues including brain and cartilage. Chondroitin sulfate proteoglycans (CSPGs) maintains the integrity of the brain extracellular matrix and major inhibitory contributors for glial scar and neural plasticity. The activity of aggrecanases in the central nervous system (CNS)has been reported. ADAMTSs are an enzyme degrading CSPGs in the brain. However, there is a little knowledge regarding ADAMTSs in the CNS. We investigated the expression levels of ADAMTSs mRNAs by RT-PCR after spinal cord injury in mouse. Transcripts encoding 4 of the 19 known ADAMTSs were evaluated in the mouse spinal cord following injury. ADAMTS1, -5 and -9 expression levels were found to be upregulated. No change was observed in ADAMTS4 expression. By means of immunohistochemistry, ADAMTSs were detected in the astrocytes implying its cellular source in SCI. Western blot analyses indicated that aggrecanase-generated proteoglycan fragments are produced after SCI. (c) 2013 Elsevier Ireland Ltd. All rights reserved.

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  • A potential association between the number of CA repeats in the promoter region of the ADAMTS9 gene with lymphatic metastasis of breast cancer

    Mikdat Bozer, Fatma Asik, Muradiye Acar, Hacer Haltas, Sibel Yenidunya, Metin Canbal, Vehap Topcu, Muhammet Ramazan Yigitoglu, Mehmet Gunduz, Esra Gunduz, Satoshi Hirohata, Kadir Demircan

    TURKISH JOURNAL OF MEDICAL SCIENCES   43 ( 5 )   671 - 677   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:TUBITAK SCIENTIFIC & TECHNICAL RESEARCH COUNCIL TURKEY  

    Aim: We investigated the effect of the number of cytosine-adenine (CA) repeats in the ADAMTS9 promoter region on breast cancer lymphatic metastasis.Materials and methods: Thirty-one postoperative breast cancer patients were selected and examined retrospectively. The patients were classified into 2 groups: metastatic or nonmetastatic. Thirty healthy women were selected as the control group, and their peripheral blood was obtained. Following DNA isolation from the cancer tissue specimens and peripheral blood, the promoter region of the ADAMTS9 gene was directly sequenced and the number of CA repeats was determined.Results: The number of CA repeats ranged between 19 and 21 in the control and metastatic groups. However, in the nonmetastatic group, the number of CA repeats ranged between 17 and 18. This difference in the median number of CA repeats between the control group and the nonmetastatic group was statistically significant.Conclusion: A potential relationship may exist between lymphatic metastasis in breast cancer and the number of CA repeats in the promoter region of the ADAMTS9 gene. Our study indicates a potential association between the number of CA microsatellite repeats in the promoter region of the ADAMTS9 gene and breast cancer lymphatic metastasis.

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  • Tumor growth inhibitory effect of ADAMTS1 is accompanied by the inhibition of tumor angiogenesis. 査読 国際誌

    Masanari Obika, Hiroko Ogawa, Katsuyuki Takahashi, Jiayi Li, Omer Faruk Hatipoglu, Mehmet Zeynel Cilek, Toru Miyoshi, Junko Inagaki, Takashi Ohtsuki, Shozo Kusachi, Yoshifumi Ninomiya, Satoshi Hirohata

    Cancer science   103 ( 10 )   1889 - 97   2012年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Angiogenesis plays an important role in tumor progression. Several reports have demonstrated that a disintegrin and metalloproteinase with thrombospondin motifs1 (ADAMTS1) inhibited angiogenesis via multiple mechanisms. The aim of this study was to investigate the effect of ADAMTS1 on endothelial cells in vitro and on tumor growth with regard to angiogenesis in vivo. We examined the effects of the transfection of ADAMTS1 using two constructs, full-length ADAMTS1 (full ADAMTS1) and catalytic domain-deleted ADAMTS1 (delta ADAMTS1). Transfection of both the full ADAMTS1 and delta ADAMTS1 gene constructs demonstrated the secretion of tagged-ADAMTS1 protein into the conditioned medium, so we examined the effects of ADAMTS1-containing conditioned medium on endothelial cells. Both types of conditioned media inhibited endothelial tube formation, and this effect was completely abolished after immunoprecipitation of the secreted protein from the medium. Both types of conditioned media also inhibited endothelial cell migration and proliferation. We then examined the impact of ADAMTS1 on endothelial cell apoptosis. Both conditioned media increased the number of Annexin V-positive endothelial cells and caspase-3 activity and this effect was attenuated when z-vad was added. These results indicated that ADAMTS1 induced endothelial cell apoptosis. We next examined the effects of ADAMTS1 gene transfer into tumor-bearing mice. Both full ADAMTS1 and delta ADAMTS1 significantly inhibited the subcutaneous tumor growth. Collectively, our results demonstrated that ADAMTS1 gene transfer inhibited angiogenesis in vitro and in vivo, likely as a result of the induction of endothelial cell apoptosis by ADAMTS1 that occurs independent of the protease activity.

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  • Serum hepatitis B virus DNA before liver transplantation correlates with HBV reinfection rate even under successful low-dose hepatitis B immunoglobulin prophylaxis 査読 国際誌

    Tetsuya Yasunaka, Akinobu Takaki, Takahito Yagi, Yoshiaki Iwasaki, Hiroshi Sadamori, Kazuko Koike, Satoshi Hirohata, Masashi Tatsukawa, Daisuke Kawai, Hidenori Shiraha, Yasuhiro Miyake, Fusao Ikeda, Haruhiko Kobashi, Hiroaki Matsuda, Susumu Shinoura, Ryuichi Yoshida, Daisuke Satoh, Masashi Utsumi, Teppei Onishi, Kazuhide Yamamoto

    HEPATOLOGY INTERNATIONAL   5 ( 4 )   918 - 926   2011年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Purpose The combination of hepatitis B immunoglobulin (HBIg) and nucleos(t)ide analogues has been accepted as the best treatment to control hepatitis B recurrence after orthotopic liver transplantation (OLT). However, the optimal dose of HBIg remains unclear. We have previously reported that high-dose HBIg in the early period followed by low-dose HBIg with nucleos(t)ide analogues offers reliable and cost-effective control of hepatitis B recurrence. The aim of this study was to investigate intrahepatic hepatitis B virus (HBV) reinfection status with our clinically successful protocol.
    Methods We quantified levels of intrahepatic HBV covalently closed circular (ccc) deoxyribonucleic acid (DNA) and serum hepatitis B core-related antigen (HBcrAg), a new serological marker that can estimate intrahepatic cccDNA levels. Nucleos(t)ide analogues were administered in all cases.
    Results No patients showed recurrence of hepatitis B surface antigen (HBsAg) or HBV-DNA. However, HBV, cccDNA, and HBcrAg were positive in 57% and 48% of patients after OLT, respectively. Pre-OLT serum HBV-DNA and HBcrAg levels correlated linearly with post-OLT cccDNA levels (r = 0.534, P &lt; 0.05, and r = 0.634, P &lt; 0.05, respectively). High serum HBV-DNA and HBcrAg levels, particularly with &gt; 3 log(10) copies/mL and &gt; 4 log(10) IU/mL, respectively, at the time of OLT, were associated with high levels of post-OLT cccDNA. Even with our successful protocol, nearly half of patients showed HBV reinfection.
    Conclusions Patients with high serum HBV-DNA and HBcrAg levels before OLT (particularly &gt; 3 log(10) copies/mL and &gt; 4 log(10) IU/mL, respectively) should be followed with care for HBV recurrence.

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  • AHR, a novel acute hypoxia-response sequence, drives reporter gene expression under hypoxia in vitro and in vivo. 査読 国際誌

    Mehmet Zeynel Cilek, Satoshi Hirohata, Omer Faruk Hatipoglu, Hiroko Ogawa, Toru Miyoshi, Junko Inagaki, Takashi Ohtsuki, Hiroshi Harada, Shigeshi Kamikawa, Shozo Kusachi, Yoshifumi Ninomiya

    Cell biology international   35 ( 1 )   1 - 8   2011年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) is an early immediate gene. We have previously reported that ADAMTS1 was strongly induced by hypoxia. In this study, we investigated whether ADAMTS1 promoter-driven reporter signal is detectable by acute hypoxia. We constructed the GFP (green fluorescent protein) expression vector [AHR (acute hypoxia-response sequence)-GFP] under the control of ADAMTS1 promoter and compared it with the constitutive GFP-expressing vector under the control of CMV (cytomegalovirus promoter-GFP). We transduced AHR-GFP and examined whether GFP signals can be detected under the acute hypoxia. When the human umbilical vein [HUVEC (human umbilical vein endothelial cells)] was transduced under normoxia, there were few GFP signals, while CMV-GFP showed considerable GFP signals. When HUVEC was stimulated with hypoxia, GFP signals from AHR-GFP gene were induced under hypoxic conditions. Notably, the GFP signals peaked at 3 h under hypoxia. In ischaemic hind limb model, transduced AHR-GFP showed hypoxic induction of GFP signals. In summary, we have demonstrated that the AHR system induced the reporter gene expression by acute hypoxia, and its induction is transient. This is the first report showing the unique acute hypoxia-activated gene expression system.

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  • Significant relationship between changes in brachial-ankle pulse wave velocity relative to blood pressure elevation and coronary artery disease 査読 国際誌

    Issei Komatsubara, Shinichi Inoue, Rie Koumoto, Shigeru Matano, Tomoki Kitawaki, Satoshi Hirohata, Toru Miyoshi, Hiroko Ogawa, Ryoko Shinohata, Shozo Kusachi

    CORONARY ARTERY DISEASE   21 ( 7 )   407 - 413   2010年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Objectives Based on well-established physiological theories, we studied correlations between changes in brachial-ankle pulse wave velocity (baPWV) relative to blood pressure (BP) elevation (elasticity of large-to-medium-sized arteries), and coronary artery disease (CAD).
    Methods The baPWV (in centimeters/second) and BP (in millimeters of mercury) were determined in 101 patients before, during, and/or after a cold pressor test using a volume-plethysmographic system.
    Results Significantly higher rates of increase in PWV relative to changes in BP were observed in the CAD(+) group than in the CAD(-) group when mean BP [median (25th-75th percentiles): 14.8 (8.3-24.9) vs. 8.6 (5.7-11.4) cm/s/mmHg, P &lt; 0.0001], and systolic [10.1 (6.0-17.5) vs. 6.4 (4.4-10.6) cm/s/mmHg, P = 0.0023] and diastolic BP [21.0 (14.0-34.4) vs. 10.8 (6.8-16.1) cm/s/mmHg, P &lt; 0.0001] were used as BP indices. Similarly, the rates of increase in baPWV showed a significant correlation with the extent of CAD. The rate of increase in baPWV obtained using the mean, systolic and diastolic BP as indices showed an area under the receiver operating characteristic curve of 0.68-0.76, sensitivity of 65-75%, and specificity of 65-75% for the detection of CAD. The area under the receiver operating characteristic curve, sensitivity, and specificity for the rate of increase were slightly higher than those for baseline baPWV and baseline baPWV/baseline BP ratio, but not to a significant degree.
    Conclusion The rate of increase in baPWV relative to BP elevation determined by cold pressor test is significantly and moderately correlated with CAD. To identify patients with CAD, the rate of increase in baPWV relative to changes in BP can provide considerable, but limited, information. Coron Artery Dis 21: 407-413 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

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  • Increased activity and expression of histone deacetylase 1 in relation to tumor necrosis factor-alpha in synovial tissue of rheumatoid arthritis 査読 国際誌

    Tomoko Kawabata, Keiichiro Nishida, Koji Takasugi, Hiroko Ogawa, Kenei Sada, Yasutaka Kadota, Junko Inagaki, Satoshi Hirohata, Yoshifumi Ninomiya, Hirofumi Makino

    Arthritis Research and Therapy   12 ( 4 )   R133   2010年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Introduction: The purpose of this study was to investigate the profile of histone deacetylase (HDAC) expression in the synovial tissue of rheumatoid arthritis (RA) compared with that of normal control and osteoarthritis (OA), and to examine whether there is a link between HDAC activity and synovial inflammation.Methods: HDAC activity and histone acetyltransferase (HAT) activity were determined in nuclear extracts of total synovial tissue surgically obtained from normal, OA and RA joints. The level of cytoplasmic tumor necrosis factor a (TNFα) fraction was measured by ELISA. Total RNA of synovial tissue was used for RT-PCR of HDAC1-8. In synovial fibroblasts from RA (RASFs), the effects of TNFα on nuclear HDAC activity and class I HDACs (1, 2, 3, 8) mRNA expressions were examined by quantitative real-time PCR. The protein expression and distribution of class I HDACs were examined by Western blotting.Results: Nuclear HDAC activity was significantly higher in RA than in OA and normal controls and correlated with the amount of cytoplasmic TNFα. The mRNA expression of HDAC1 in RA synovial tissue was higher than in OA and normal controls, and showed positive correlation with TNFα mRNA expression. The protein level of nuclear HDAC1 was higher in RA synovial tissue compared with OA synovial tissue. Stimulation with TNFα significantly increased the nuclear HDAC activity and HDAC1 mRNA expression at 24 hours and HDAC1 protein expression at 48 hours in RASFs.Conclusions: Our results showed nuclear HDAC activity and expression of HDAC1 were significantly higher in RA than in OA synovial tissues, and they were upregulated by TNFα stimulation in RASFs. These data might provide important clues for the development of specific small molecule HDAC inhibitors. © 2010 Kawabata et al.
    licensee BioMed Central Ltd.

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  • Serum adipocyte fatty acid-binding protein is independently associated with coronary atherosclerotic burden measured by intravascular ultrasound 査読 国際誌

    Toru Miyoshi, Go Onoue, Atsushi Hirohata, Satoshi Hirohata, Shinichi Usui, Kazuyoshi Hina, Hiroshi Kawamura, Masayuki Doi, Kengo Fukushima Kusano, Shozo Kusachi, Yoshifumi Ninomiya

    ATHEROSCLEROSIS   211 ( 1 )   164 - 169   2010年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    Objectives: Adipocyte fatty acid-binding protein (A-FABP) has been shown to have an effect on insulin resistance, lipid metabolism, and atherosclerosis in animals. We therefore investigated the association between the serum A-FABP level and coronary atherosclerosis.
    Methods: One hundred twenty-five consecutive patients with coronary artery disease (CAD) were enrolled after coronary angiography. Plaque volume in non-culprit coronary arteries was determined using intravascular ultrasound and expressed as percent plaque volume (%PV). Voluntary blood donors (n = 120), matched for age and gender, served as controls. Serum levels of A-FABP, adiponectin, and inflammatory markers were measured by enzyme-linked immunosorbent assay.
    Results: The serum A-FABP level in CAD patients was significantly higher than in control subjects (median [25th-75th percentiles], 27.2 [20.5-37.1] ng/mL vs. 18.9 [14.6-24.5] ng/mL) (p &lt; 0.01). Serum A-FABP showed 0.74 of the area under the curve in the receiver operating characteristic curve for the detection of CAD, with 76% specificity and 65% sensitivity with a cut-off value of 20.1 ng/mL. Further, in CAD patients, serum A-FABP had a significant correlation with %PV in all subjects (r = 0.33, p &lt; 0.01). Serum A-FABP was positively correlated with the body mass index, serum interleukin-6 and high-sensitive CRP, and negatively correlated with HDL-cholesterol and serum adiponectin in CAD patients. Stepwise regression analysis revealed that serum A-FABP was independently associated with %PV.
    Conclusion: Increased serum A-FABP was significantly associated with a greater coronary plaque burden. Our findings revealed that the measurement of serum A-FABP could be utilized for the evaluation of the extent of coronary atherosclerosis. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

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  • Type IV Collagen Induces Expression of Thrombospondin-1 that is Mediated by Integrin alpha 1 beta 1 in Astrocytes 査読 国際誌

    Tomoko Yonezawa, Shunji Hattori, Junko Inagaki, Masae Kurosaki, Tomoyuki Takigawa, Satoshi Hirohata, Toru Miyoshi, Yoshifumi Ninomiyai

    GLIA   58 ( 7 )   755 - 767   2010年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Following brain injury, thrombospondin-1 (TSP-1) is involved in angiogenesis and synaptic recovery. In this study, we used a cold injury-model and found that TSP-1 mRNA was markedly upregulated after brain injury. Immunohistochemistry showed that TSP-1 was upregulated in both the core of the lesion and in the perilesional area of injured brain tissue. Numerous astrocytes immunopositive for glial fibrillary acidic protein (GFAP) were found in the perilesional area, and TSP-1 was also expressed in almost all astrocytes surrounding blood vessels at 4 days after injury. Next, we examined the influence of vascular basement membrane components on TSP-1 expression. When astrocytes were cultured on type IV collagen, TSP-1 was significantly upregulated compared with the expression when cells were grown on lamin, fibronectin, or poly-L-lysine. This increase occurred exclusively when astrocytes were grown on the native form of type IV collagen but not on the heat-denatured form or the non-collagenous 1 domain. Further, integrin alpha 1 and beta 1 mRNAs were upregulated concomitantly with GFAP mRNA, and integrin alpha 1 protein was localized to the endfeet of astrocytes that surrounded blood vessels in the injured brain. Using function-blocking antibodies, we found that the effect of type IV collagen was attributed to integrin alpha 1 beta 1 in primary astrocytes. Collectively, our results suggest that vascular basement membrane components substantially impact gene expression in astrocytes during brain tissue repair. (C) 2010 Wiley-Liss, Inc.

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  • Combination Therapy of Calcium Channel Blocker and Angiotensin II Receptor Blocker Reduces Augmentation Index in Hypertensive Patients 査読 国際誌

    Masayuki Doi, Toru Miyoshi, Satoshi Hirohata, Shigeshi Kamikawa, Shinichi Usui, Youko Kaji, Kosuke Sakane, Hiroko Ogawa, Yoshifumi Ninomiya, Shozo Kusachi

    AMERICAN JOURNAL OF THE MEDICAL SCIENCES   339 ( 5 )   433 - 439   2010年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Introduction: The optimal combination treatment for hypertension has not been established. We investigated the effect of a calcium channel blocker or a diuretic added to angiotensin II receptor blockers (ARBs) on the augmentation index (AI), as a marker of arterial stiffness and wave reflection, in hypertensive patients. Methods: Thirty-seven patients treated with ARBs were randomly allocated to either of the 2 groups receiving an ARB plus azelnidipine (AZ group) or trichlormethiazide (TCM group). Changes in brachial blood pressure (BP), AI, high-sensitive C-reactive protein (hsCRP), and serum asymmetric dimethylarginine, as an endogenous nitric oxide synthase inhibitor, were determined. Results: Systolic and diastolic blood pressure after 6 months were significantly reduced in both the groups similarly; however, after adjustment for baseline covariates, the extent of the reduction in AI (%) in the AZ group was significantly greater than in the TCM group (between-group difference was 3.2; 95% CI: 0.2-6.3; P = 0.03). The reduction of high-sensitive C-reactive protein (mg/L) and serum asymmetric dimethylarginine (mu mol/L) was significantly greater in the AZ group than in the TCM group (between-group difference was 0.18 and 0.05; 95% CI: -0.01 to 0.36 and -0.01 to 0.11; P = 0.04 and 0.02, respectively). Further, when patients were analyzed according to age younger than 60 years or older than 60 years, the reduction in AI in the AZ group aged older than 60 years was significantly greater than in the TCM group. Conclusion: The results suggest that azelnidipine has a more beneficial effect on vascular properties in combination therapy with ARB than trichlormethiazide.

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  • Impact of Olmesartan on Progression of Coronary Atherosclerosis A Serial Volumetric Intravascular Ultrasound Analysis From the OLIVUS (Impact of OLmesarten on progression of coronary atherosclerosis: evaluation by IntraVascular UltraSound) Trial 査読 国際誌

    Atsushi Hirohata, Keizo Yamamoto, Toru Miyoshi, Kunihiko Hatanaka, Satoshi Hirohata, Hitoshi Yamawaki, Issei Komatsubara, Masaaki Murakami, Eiki Hirose, Shinji Sato, Keisuke Ohkawa, Makoto Ishizawa, Hirosuke Yamaji, Hiroshi Kawamura, Shozo Kusachi, Takashi Murakami, Kazuyoshi Hina, Tohru Ohe

    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY   55 ( 10 )   976 - 982   2010年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE INC  

    Objectives The aim of this study was to evaluate the impact of olmesartan on progression of coronary atherosclerosis.
    Background Prior intravascular ultrasound (IVUS) trial results suggest slowing of coronary atheroma progression with some medicines but have not shown convincing evidence of regression with angiotension-II receptor blocking agents.
    Methods A prospective, randomized, multicenter trial-OLIVUS (Impact of OLmesartan on progression of coronary atherosclerosis: evaluation by IntraVascular UltraSound)-was performed in 247 stable angina pectoris patients with native coronary artery disease. When these patients underwent percutaneous coronary intervention for culprit lesions, IVUS was performed in their nonculprit vessels (without angiographically documented coronary stenosis [&lt;50%]). Patients were randomly assigned to receive 10 to 40 mg of olmesartan or control and treated with a combination of beta-blockers, calcium channel blockers, diuretics, nitrates, glycemic control agents, and/or statins per physician's guidance. Serial IVUS examinations (baseline and 14-month follow-up) were performed to assess coronary atheroma volume. Volumetric IVUS analyses included lumen, plaque, vessel volume, percent atheroma volume (PAV), percent change in total atheroma volume (TAV) and PAV.
    Results Patient characteristics and blood pressure control were identical between the 2 groups. However, follow-up IVUS showed significantly decreased TAV and percent change in PAV in the olmesartan group (5.4% vs. 0.6% for TAV and 3.1% vs. -0.7% for percent change in PAV, control vs. olmesartan, p &lt; 0.05 for all).
    Conclusions These observations suggest a positive role in a potentially lower rate of coronary atheroma progression through the administration of olmesartan, an angiotension-II receptor blocking agent, for patients with stable angina pectoris. (J Am Coll Cardiol 2010; 55: 976-82) (C) 2010 by the American College of Cardiology Foundation

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  • Effect of Cilnidipine on Normal to Marginally Elevated Urine Albumin-Creatinine Ratio in Asymptomatic Non-Diabetic Hypertensive Patients An Exponential Decay Curve Analysis 査読 国際誌

    Takaaki Nakatsu, Shinji Toyonaga, Keiichi Mashima, Yoko Yuki, Aya Nishitani, Hiroko Ogawa, Toru Miyoshi, Satoshi Hirohata, Reishi Izumi, Shozo Kusachi

    CLINICAL DRUG INVESTIGATION   30 ( 10 )   699 - 706   2010年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ADIS INT LTD  

    Background: High-normal urinary albumin excretion has been reported to have clinical significance with respect to progression of proteinuria and hypertension.
    Objective: We analysed the effect of cilnidipine (10 mg/day) on morning systolic blood pressure (SBP) and urine albumin-creatinine ratio (UACR) in 16 non-diabetic hypertensive patients with a normal to marginally elevated UACR (mean +/- SD 29.4 +/- 21.7; range 7.5-72.9 mg/g creatinine).
    Methods: Sequential home BP and UACR data were fitted to a simple exponential function as follows: y = alpha.e(-t/beta) + gamma, where y is SBP (mmHg) or UACR (mg/g creatinine); alpha is the extent of the SBP (mmHg)- or UACR (mg/g creatinine)-lowering effect; 13 (days) is the time-constant for SBP or UACR decrease; t is the number of days after the start of cilnidipine administration; and gamma is the finally stabilized SBP (mmHg) or UACR (mg/g creatinine).
    Results: Mean +/- SD morning SBP and UACR decreased by 20.4 +/- 11.4 mmHg and 15.2 +/- 13.1 mg/g creatinine, respectively, as determined by coefficient alpha. The mean SD time-constant for UACR decrease was significantly longer than that for BP decrease (43.5 +/- 22.9 vs 15.4 +/- 7.1 days). UACR reduction correlated with pre-treatment UACR values (correlation coefficient [R] = 0.88, p &lt; 0.01) but not with BP decrease.
    Conclusions: The present study demonstrated that cilnidipine reduced UACR in hypertensive patients with normal to marginally elevated UACR independent of its BP-lowering effect.

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  • Cardio-Ankle Vascular Index is Independently Associated with the Severity of Coronary Atherosclerosis and Left Ventricular Function in Patients with Ischemic Heart Disease 査読

    Toru Miyoshi, Masayuki Doi, Satoshi Hirohata, Kosuke Sakane, Shigeshi Kamikawa, Tomoki Kitawaki, Youko Kaji, Kengo Fukushima Kusano, Yoshifumi Ninomiya, Shozo Kusachi

    JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS   17 ( 3 )   249 - 258   2010年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAPAN ATHEROSCLEROSIS SOC  

    Aim: The cardio-ankle vascular index (CAVI) has been proposed as a new noninvasive marker of arterial stiffness independent of blood pressure. We investigated the association of the CAVI with coronary atherosclerosis and left ventricular (LV) systolic and diastolic function in patients with ischemic heart disease (IHD).
    Methods: A total of 206 consecutive subjects undergoing coronary angiography were enrolled. CAVI measurement and echocardiography were performed simultaneously. Patients having significant coronary stenosis were classified into the IHD group.
    Results: CAVI in the IHD group (n = 133) was significantly higher than in the non-IHD group (n = 73) (9.1 +/- 1.3 vs. 8.7 +/- 1.2, p = 0.02). In all IHD patients, CAVI was negatively correlated with LV ejection fraction (LVEF) (r = -0.31, p &lt; 0.01), LV mass index (r = 0.24, p &lt; 0.01) and angiographic scores of coronary atherosclerosis. Stepwise regression analysis revealed that CAVI was independently associated with LVEF, along with a history of myocardial infarction, LV mass index, and left atrial diameter in all IHD patients (p &lt; 0.01). In the sub-analysis of IHD patients with preserved LVEF, CAVI was correlated with echocardiographic parameters regarding LV diastolic function. Multivariate analysis demonstrated that the increased CAVI was significantly associated with LV diastolic dysfunction in patients with preserved LVEF.
    Conclusion: CAVI, a new parameter of aortic stiffness, was independently associated with LV systolic and diastolic function as well as coronary artery disease in IHD patients.

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  • Hyaluronan receptors involved in cytokine induction in monocytes 査読 国際誌

    Hitoshi Yamawaki, Satoshi Hirohata, Toru Miyoshi, Katsuyuki Takahashi, Hiroko Ogawa, Ryoko Shinohata, Kadir Demircan, Shozo Kusachi, Kazuhide Yamamoto, Yoshifumi Ninomiya

    GLYCOBIOLOGY   19 ( 1 )   83 - 92   2009年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS INC  

    During inflammation, lower molecular weight fragments of hyaluronan accumulate, and this is known to be inflammatory and immune-stimulatory. In diseases such as inflammatory bowel disease, inflammatory cells bind to hyaluronan; however, the cellular response and molecular mechanism of hyaluronan-hyaluronan receptor interactions in mononuclear cells are not well understood. The expression of hyaluronan receptors in peripheral blood mononuclear cells (PBMC) was examined. PBMC were stimulated with lower and higher molecular weight hyaluronan (molecular weight 100-150 kDa and 2700 kDa) and the induction of proinflammatory cytokines (interleukin-6 (IL-6) and monocyte chemoattractant protein (MCP-1)) was compared by enzyme-linked immunoabsorbant assay (ELISA). Cells were coincubated with various signaling pathway inhibitors. In addition, neutralizing antibodies against CD44 and TLR4 were added and the effects on PBMC were investigated. Finally, mononuclear cells from CD44-null and toll-like receptor 4 (TLR4) mutant mice were both stimulated with lower molecular weight hyaluronan. Among the hyaluronan receptors, TLR4 and CD44 were markedly expressed on PBMC. Hyaluronan-stimulated PBMC enhanced the attachment to the extracellular matrix. Lower molecular weight hyaluronan induced IL-6 and MCP-1 production in PBMC, but high-molecular-weight hyaluronan did not induce IL-6 and MCP-1 production. An anti-CD44 antibody attenuated the induction of both IL-6 and MCP-1 in lower molecular weight hyaluronan-stimulated PBMC. In both TLR4 mutant and CD44-null mice, the induction of IL-6 by lower molecular weight hyaluronan stimulation was decreased. SB203580 completely abolished IL-6 production in both TLR4 mutant and CD44-null mononuclear cells, while PD98059 abolished IL-6 production in CD44-null mononuclear cells. Hyaluronan receptors, CD44 and TLR4, play distinct roles in cytokine induction in hyaluronan-stimulated mononuclear cells.

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  • Higher incidence and serum levels of minor cardiac biomarker elevation in sirolimus-eluting stent (Cypher) than bare metal stent implantations 査読 国際誌

    Tetsushi Seitou, Masaaki Murakami, Issei Komatsubara, Hiroshi Kawamura, Keizo Yamamoto, Kazuyoshi Hina, Satoshi Hirohata, Ryoko Shinohata, Yoshifumi Ninomiya, Shozo Kusachi

    CORONARY ARTERY DISEASE   19 ( 2 )   63 - 69   2008年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Objectives Minor cardiac biomarker elevation after percutaneous coronary intervention has long-term prognostic significance. The sirolimus-eluting stent (Cypher) has been reported to require high postinflation pressure for optimal implantation. We examined the incidence of minor cardiac biomarker elevation induced by Cypher implantation.
    Methods We measured the serum concentration of cardiac troponin-I (cTnl) 24 h after stenting and those of creatine kinase isoenzyme MB and creatine kinase before, immediately after, and 6, 12 and 24 h after implantation in patients who underwent Cypher stent (CS group; n = 53) or bare metal stent (BMS group; n = 57) implantation.
    Results No significant difference in clinical background was observed between the two groups. When a cutoff cTnl value of 0.50ng/ml was used, the CS group showed a significantly higher incidence of cTnl elevation (35.8%, 19/53) than the BMS group (14.0%, 8/57) (P&lt;0.05). Similarly, the incidence of cTnl &gt;= 0.03 ng/ml tended to be higher in the CS group (88.7%, 47/53) than in the BMS group (73.7%, 42/57: 0.05&lt;P&lt;0.10). Furthermore, the CS group showed significantly higher cTnl levels than the BMS group (1.32 +/- 2.38 vs. 0.34 +/- 0.91 ng/ml. P&lt; 0.001). Essentially, similar results were obtained for serum creatine kinase isoenzyme MB and creatine kinase. Among clinical, lesion and procedural characteristics, postinflation pressure for stenting was significantly higher only in the CS group (18.2 +/- 2.8 atm) than in the BMS group (14.0 +/- 2.7 atm) (P&lt; 0.001).
    Conclusions The results demonstrated that CS implantation increases the incidence of minor cardiac biomarker elevation compared with BMS. The difference in postinflation pressure could account for the results.

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  • Osteogenic protein-1 reduces intercellular adhesion molecule-1 messenger RNA expression, infarct size and TUNEL-positive cardiomyocytes in ischemia/reperfusion rat hearts. 査読 国際誌

    Hayashi J, Kusachi S, Murakami T, Miyoshi T, Nakamura K, Koten K, Ogawa H, Hirohata S, Ninomiya Y, Shiratori Y

    Experimental and clinical cardiology   8 ( 4 )   195 - 200   2003年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Intense response of heart rate with pronounced suppression of high-frequency power of heart rate variability to early morning exercise with high-intensity load 査読 国際誌

    J Ueta, T Nakatsu, T Murakami, S Toyonaga, S Hirohata, K Mashima, M Sangawa, S Kusachi, Y Shiratori

    BIOMEDICINE & PHARMACOTHERAPY   56 ( SUPPL. 2 )   353S - 358S   2002年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER  

    Autonomic nerve activity shows circadian variation. Therefore, we put forward the hypothesis that the responses of heart rate (HR) and high-frequency (HF) power of HR variability to exercise would be different between-early morning and daytime exercise. We performed ergometer constant load exercise tests [50 watts (low), 100 watts (high load)] in the early morning and during the day in 6 healthy volunteers. The HR response was fitted to an exponential hyperbolic sine function: HR = alpha*e(-beta*t) *sinh(omega*t)+gamma. In this equation, the beta/omega ratio was inversely correlated with the intensity of the HR response. HF power was determined using a recently developed algorithm with high time-resolution power. There were no significant differences in HR, HF power or systolic blood pressure (BP) pressure before exercise between early morning and daytime exercise with either the 50 or 100 watt loads. During exercise, there were no significant differences in maximal HR or maximal systolic BP between early morning and daytime exercise with either 50 or 100 watt loads. For high-load exercise, the beta/omega ratio was significantly lower in early morning exercise (mean+/-SD, 0.945+/-0.02) than in daytime exercise (0.987+/-0.03). Similarly, for 100 watt exercise, HF power of HR variability was significantly lower in early morning exercise (0.94+/-0.52 msec[Hz(1/2)) than in daytime exercise (1.26+/-0.74 msec/Hz(1/2)). In conclusion, the present study demonstrated that a lower beta/omega ratio in the HR response was associated with lower HF power of HR variability in early morning high-load exercise compared to that in daytime exercise, indicating that the heart rate responded more intensely to early morning exercise than to daytime exercise with a high load due, at least partly, to pronounced suppression of parasympathetic nerve activity. (C) 2002 Editions scientifiques et medicales Elsevier SAS. All rights reserved.

    DOI: 10.1016/s0753-3322(02)00316-5

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  • Spatial changes of gelatinolytic activity in myocardial infarction in rats

    Takashi Murakami, Shozo Kusachi, Satoshi Hirohata, Chisato Suezawa, Syunji Takemoto, Satoshi Sezaki, Takao Tsuji, Yoshifumi Ninomiyal

    Keio Journal of Medicine   50   54 - 63   2001年1月

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.2302/kjm.50.supplement3_54

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  • ADAMTS family - New extracellular matrix degrading enzyme

    S. Hirohata

    Seikagaku   73 ( 11 )   1333 - 1337   2001年

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書籍等出版物

  • 平成18-19年度科学研究費補助金(基盤研究(B))研究成果報告書

    2008年 

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  • 平成16-17年度科学研究費補助金(基盤研究(C))研究成果報告書

    2006年 

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  • 平成16-17年度科学研究費補助金(基盤研究(B))研究成果報告書

    2006年 

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  • 平成17年度文部科学省補助事業成果報告書 医療・福祉・健康関連ミクロものづくり共同研究事業 ナノバイオテクノロジーに基づく新しい標的医療の創造とその基盤研究

    2006年 

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  • 平成15-16年度科学研究費補助金(基盤研究(B))研究成果報告書

    2005年 

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  • 平成14-15年度科学研究費補助金(基盤研究B)成果報告書

    2004年 

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  • 平成13-14年度科学研究費補助金(基盤研究B)成果報告書

    2003年 

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  • Advancement of Life Science

    Roan AMVO Publishing Company, Taipei  2003年 

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MISC

  • 変形性関節症関連microRNAの検索並びに解析

    大月 孝志, オメル・ファルク・ハティポール, 品岡 玲, メフメット・ゼイネル・チレッキ, 西村 拓人, 浅野 恵一, 稲垣 純子, 大橋 俊孝, 西田 圭一郎, 岡田 保典, 廣畑 聡

    日本結合組織学会学術大会プログラム・抄録集   50回   111 - 111   2018年6月

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    記述言語:日本語   出版者・発行元:日本結合組織学会  

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  • RNA干渉法による特発性肺線維症に重要な分子のサイレンシング

    ハティポール・オメル・ファルク, エユプ・ウチュテペ, グンデゥズ・エスラ, グンデゥズ・メーメット, 大月 孝志, 稲垣 純子, 廣畑 聡

    日本結合組織学会学術大会プログラム・抄録集   50回   146 - 146   2018年6月

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  • Differences in activated clotting time and initial heparin dosage during atrial fibrillation ablation for patients with edoxaban compared with warfarin.

    Yamaji H, Murakami T, Hina K, Higashiya S, Kawamura H, Murakami M, Kamikawa S, Hirohata S, Kusachi S

    J Cardiovasc Electrophysiol   29 ( 6 )   835 - 843   2018年

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  • Stromal Versican Regulates Tumor Growth by Promoting Angiogenesis 国際誌

    Keiichi Asano, Courtney M. Nelson, Sumeda Nandadasa, Noriko Aramaki-Hattori, Daniel J. Lindner, Tyler Alban, Junko Inagaki, Takashi Ohtsuki, Toshitaka Oohashi, Suneel S. Apte, Satoshi Hirohata

    SCIENTIFIC REPORTS   7 ( 1 )   2101 - 2105   2017年12月

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    記述言語:英語   出版者・発行元:NATURE PUBLISHING GROUP  

    The proteoglycan versican is implicated in growth and metastases of several cancers. Here we investigated a potential contribution of stromal versican to tumor growth and angiogenesis. We initially determined versican expression by several cancer cell lines. Among these, MDA-MB231 and B16F10 had none to minimal expression in contrast to Lewis lung carcinoma (LLC). Notably, tumors arising from these cell lines had higher versican levels than the cell lines themselves suggesting a contribution from the host-derived tumor stroma. In LLC-derived tumors, both the tumor and stroma expressed versican at high levels. Thus, tumor stroma can make a significant contribution to tumor versican content. Versican localized preferentially to the vicinity of tumor vasculature and macrophages in the tumor. However, an ADAMTS protease-generated versican fragment uniquely localized to vascular endothelium. To specifically determine the impact of host/stroma-derived versican we therefore compared growth of tumors from B16F10 cells, which produced littleversican, in Vcan(hdf/+) mice and wild-type littermates. Tumors in Vcan(hdf/+) mice had reduced growth with a lower capillary density and accumulation of capillaries at the tumor periphery. These findings illustrate the variability of tumor cell line expression of versican, and demonstrate that versican is consistently contributed by the stromal tissue, where it contributes to tumor angiogenesis.

    DOI: 10.1038/s41598-017-17613-6

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  • 炎症性サイトカイン誘導性マトリックス分解酵素発現のイオンチャネルを介した抑制とその機構解析

    大月 孝志, 品岡 玲, 品岡 加苗, Mehmet Cilek, Omer Hatipoglu, 西村 拓人, 稲垣 純子, 西田 圭一郎, 廣畑 聡

    生命科学系学会合同年次大会   2017年度   [3P - 1164]   2017年12月

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    記述言語:英語   出版者・発行元:生命科学系学会合同年次大会運営事務局  

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  • Circulating adipocyte fatty acid-binding protein is a predictor of cardiovascular events in patients with stable angina undergoing percutaneous coronary intervention 国際誌

    Wataru Takagi, Toru Miyoshi, Masayuki Doi, Keisuke Okawa, Kazumasa Nosaka, Tomoyuki Nishibe, Naoaki Matsuo, Satoshi Hirohata, Hiroshi Ito

    BMC CARDIOVASCULAR DISORDERS   17 ( 1 )   83 - 106   2017年10月

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    記述言語:英語   出版者・発行元:BIOMED CENTRAL LTD  

    Background: Adipocyte fatty acid-binding protein (A-FABP) is expressed in both adipocytes and macrophages. Recent studies have shown that A-FABP is secreted by adipocytes and that the A-FABP concentration is associated with obesity, insulin resistance, and atherosclerosis. We have reported that the coronary atherosclerotic burden is associated with the serum A-FABP concentration. In the present study, we investigated whether the serum A-FABP concentration is associated with prognosis in patients with stable angina pectoris who have undergone percutaneous coronary intervention (PCI).
    Methods: This was a prospective single-center trial. In total, 130 patients with stable angina pectoris undergoing their first PCI were enrolled from August 2008 to July 2010 at Kagawa Prefectural Central Hospital. The primary endpoints were cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, revascularization, and hospitalization for heart failure.
    Results: During the follow-up (median, 50 months; interquartile range, 23-66 months), 49 cardiovascular events occurred. Kaplan-Meier analysis showed that the cumulative incidence of the primary endpoints in the high AFABP group (median A-FABP concentration of &gt;= 18.6 ng/ml) was greater than that in the low A-FABP group. Cox analysis showed that the A-FABP concentration was an independent predictor of cardiovascular events adjusted for age and the presence of multi-vessel disease (hazard ratio, 1.03; 95% confidence interval, 1.01-1.04; p = 0.01).
    Conclusion: The serum A-FABP concentration is associated with prognosis in patients with stable angina undergoing PCI, suggesting that the serum A-FABP concentration could be useful for risk assessment of secondary prevention.

    DOI: 10.1186/s12872-017-0691-2

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  • EPA/AA CAN BE A PREDICTIVE FACTOR IN THE PATIENTS WITH CORONARY ARTERY DISEASE IN THE STRONG STATIN ERA

    Naoaki Matsuo, Atsushi Takaishi, Nobuhiko Oonishi, Yukari Nakano, Kenzou Kagawa, Tatsuya Yamaji, Yuuichi Katou, Kazuna Hayashi, Masayuki Ueeda, Satoshi Hirohata

    ATHEROSCLEROSIS   263   E196 - E197   2017年8月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER IRELAND LTD  

    DOI: 10.1016/j.atherosclerosis.2017.06.632

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  • がん微小環境の実体 がん微小環境におけるバーシカン分解酵素ADAMTSの局在と血管新生におけるバーシカンの意義

    浅野 恵一, 廣畑 聡, 大月 孝志, オメル・ファルク・ハティポール, 稲垣 純子, 大橋 俊孝

    日本結合組織学会学術大会プログラム・抄録集   49回   56 - 56   2017年6月

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    記述言語:日本語   出版者・発行元:日本結合組織学会  

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  • 関節の修復・再生 メカニカルストレスの軟骨細胞に及ぼす多彩な作用 マトリックス合成促進と炎症性サイトカイン誘導性マトリックス分解活性抑制

    大月 孝志, 品岡 玲, 熊岸 加苗, 岡, メフメット・ゼイネル・チレッキ, オメル・ファルク・ハティポール, 稲垣 純子, 西田 圭一郎, 廣畑 聡

    日本結合組織学会学術大会プログラム・抄録集   49回   62 - 62   2017年6月

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    記述言語:日本語   出版者・発行元:日本結合組織学会  

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  • A rapid and precise method for measuring plasma apoE-rich HDL using polyethylene glycol and cation-exchange chromatography: a pilot study on the clinical significance of apoE-rich HDL measurements.(共著)

    Ikeda T, Shinohata R, Murakami M, Hina K, Kamikawa S, Hirohata S, Kusachi S, Tamura A, Usui S

    clin chim Acta   465   112 - 118   2017年2月

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  • Early initiation of eicosapentaenoic acid and statin treatment is associated with better clinical outcomes than statin alone in patients with acute coronary syndromes: 1-year outcomes of a randomized controlled study 国際誌

    Kazumasa Nosaka, Toru Miyoshi, Mutsumi Iwamoto, Masahito Kajiya, Keisuke Okawa, Saori Tsukuda, Fumi Yokohama, Masahiro Sogo, Tomoyuki Nishibe, Naoaki Matsuo, Satoshi Hirohata, Hiroshi Ito, Masayuki Doi

    INTERNATIONAL JOURNAL OF CARDIOLOGY   228   173 - 179   2017年2月

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    Background: Early initiation of EPA treatment in combination with a statin within 24 h after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (MI) reduces inflammation and ventricular arrhythmia compared with statin monotherapy; however, the impact of early initiation of EPA treatment on cardiovascular events is unclear. We determined whether early eicosapentaenoic acid (EPA) treatment in patients with acute coronary syndrome (ACS) reduces adverse cardiovascular events.
    Methods: This prospective, open-label, blind end point-randomized trial consisted of 241 patients with ACS. Patients were randomly assigned to receive pitavastatin (2mg/day) with or without 1800mg/day of EPA initiated within 24 h after PCI. The primary endpoint was defined as cardiovascular events occurring within 1 year, including death from a cardiovascular cause, nonfatal stroke, nonfatal MI and revascularization.
    Results: The mean EPA/ arachidonic acid ratio at follow-up was 0.40 in the control group and 1.15 in the EPA group. A primary endpoint event occurred in 11 patients (9.2%) in the EPA group and 24 patients (20.2%) in the control group (absolute risk reduction, 11.0%; hazard ratio, 0.42; 95% confidence interval, 0.21 to 0.87; P = 0.02). Notably, death from a cardiovascular cause at 1 year was significantly lower in the EPA group than in the control group (0.8% vs. 4.2%, P = 0.04).
    Conclusions: Early initiation of treatment with EPA combined with statin after successful primary PCI reduced cardiovascular events after ACS. (C) 2016 The Authors. Published by Elsevier Ireland Ltd.

    DOI: 10.1016/j.ijcard.2016.11.105

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  • 細胞外マトリックス分解酵素ADAMTS1の多様性

    廣畑 聡, 稲垣純子, 大月孝志

    薬学雑誌   37 ( 7 )   811 - 814   2017年

  • Diverse Functions of a Disintegrin and Metalloproteinase with Thrombospondin Motif-1.(共著)

    Hirohata S, Inagaki J, Ohtsuki T

    Yakugaku Zasshi   137 ( 7 )   811 - 814   2017年

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  • MMP-13 is constitutively produced in human chondrocytes and co-endocytosed with ADAMTS-5 and TIMP-3 by the endocytic receptor LRP1

    Kazuhiro Yamamoto, Hiroshi Okano, Wakako Miyagawa, Robert Visse, Yasuyuki Shitomi, Salvatore Santamaria, Jayesh Dudhia, Linda Troeberg, Dudley K. Strickland, Satoshi Hirohata, Hideaki Nagase

    MATRIX BIOLOGY   56   57 - 73   2016年12月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE BV  

    Matrix metalloproteinase 13 (MMP-13) degrades collagenous extracellular matrix and its aberrant activity associates with diseases such as arthritis, cancer, atherosclerosis and fibrosis. The wide range of MMP-13 proteolytic capacity suggests that it is a powerful, potentially destructive proteinase and thus it has been believed that MMP-13 is not produced in most adult human tissues in the steady state. Present study has revealed that human chondrocytes isolated from healthy adults constitutively express and secrete MMP-13, but that it is rapidly endocytosed and degraded by chondrocytes. Both pro- and activated MMP-13 bind to clusters II and III of low-density lipoprotein (LDL) receptor-related protein 1 (LRP1). Domain deletion studies indicated that the hemopexin domain is responsible for this interaction. Binding competition between MMP-13 and ADAMTS-4,-5 or TIMP-3, which also bind to cluster II, further shown that the MMP-13 binding site within cluster II is different from those of ADAMTS-4,-5 or TIMP-3. MMP-13 is therefore co-endocytosed with ADAMTS-5 and TIMP-3 by human chondrocytes. These findings indicate that MMP-13 may play a role on physiological turnover of cartilage extracellular matrix and that LRP1 is a key modulator of extracellular levels of MMP-13 and its internalization is independent of the levels of ADAMTS-4,-5 and TIMP-3. (C) 2016 The Authors. Published by Elsevier B.V.

    DOI: 10.1016/j.matbio.2016.03.007

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  • Loss of ADAMTS4 reduces high fat diet-induced atherosclerosis and enhances plaque stability in ApoE(-/-) mice 国際誌

    Saran Kumar, Mo Chen, Yan Li, Fiona H. S. Wong, Chung Wee Thiam, Md Zakir Hossain, Kian Keong Poh, Satoshi Hirohata, Hiroko Ogawa, Veronique Angeli, Ruowen Ge

    SCIENTIFIC REPORTS   6   31130 - 31130   2016年8月

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    記述言語:英語   出版者・発行元:NATURE PUBLISHING GROUP  

    Atherosclerosis is a chronic inflammatory disease characterized by formation of lipid-rich plaques on the inner walls of arteries. ADAMTS4 (a disintegrin-like and metalloproteinase with thrombospondin motifs-4) is a secreted proteinase that regulates versican turnover in the arterial wall and atherosclerotic plaques. Recent reports indicated elevated ADAMTS4 level in human atherosclerotic plaques and in the plasma of acute coronary syndrome patients. Nevertheless, whether increased ADAMTS4 is a consequence of atherosclerosis or ADAMTS4 has a causal role in atherogenesis remains unknown. In this work, we investigated the role of ADAMTS4 in diet induced atherosclerosis using apolipoprotein E deficient (ApoE(-/-)) and Adamts4 knockout mice. We show that ADAMTS4 expression increases in plaques as atherosclerosis progresses in ApoE(-/-) mice. ApoE(-/-) Adamts4(-/-) double knockout mice presented a significant reduction in plaque burden at 18 weeks of age. Loss of ADAMTS4 lead to a more stable plaque phenotype with a significantly reduced plaque vulnerability index characterized by reduced lipid content and macrophages accompanied with a significant increase in smooth muscle cells, collagen deposition and fibrotic cap thickness. The reduced atherosclerosis is accompanied by an altered plasma inflammatory cytokine profile. These results demonstrate for the first time that ADAMTS4 contributes to diet induced atherosclerosis in ApoE(-/-) mice.

    DOI: 10.1038/srep31130

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  • 変形性関節症へのヒアルロン酸投与、いつ投与すべきか? 動物モデルからの知見

    大月 孝志, 品岡 玲, 熊岸 加苗, 河野 真優美, 篠原 真歩, 浅野 恵一, 稲垣 純子, 大橋 俊孝, 西田 圭一郎, 廣畑 聡

    日本結合組織学会学術大会プログラム・抄録集   48回   60 - 60   2016年6月

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    記述言語:日本語   出版者・発行元:日本結合組織学会  

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  • Subclavian steal syndrome: a case report and review of advances in diagnostic and treatment approaches.

    Komatsubara I, Kondo J, Akiyama M, Takeuchi H, Nogami K, Usui S, Hirohata S, Kusachi S

    Cardiovasc Revasc Med.   17 ( 1 )   54 - 58   2016年

  • 伸展刺激の強度による細胞外マトリックスタンパクおよびマトリックス分解酵素発現への影響

    大月 孝志, 金道 幸子, 長谷川 みさ, 稲垣 純子, 浅野 恵一, 障子 友理, 熊岸 加苗, 西田 圭一郎, 大橋 俊孝, 廣畑 聡

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   88回・38回   [2P0078] - [2P0078]   2015年12月

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    記述言語:日本語   出版者・発行元:(公社)日本生化学会  

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  • Interleukin-1β induced nuclear factor-κB binds to a disintegrin-like and metalloproteinase with thrombospondin type 1 motif 9 promoter in human chondrosarcoma cells.

    Altuntas A, Halacli SO, Cakmak O, Erden G, Akyol S, Ugurcu V, Hirohata S, Demircan K

    Mol Med Rep   12 ( 1 )   595 - 600   2015年7月

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  • Eosinophil Cationic Protein Shows Survival Effect on H9c2 Cardiac Myoblast Cells with Enhanced Phosphorylation of ERK and Akt/GSK-3β under Oxidative Stress.

    Ishii H, Kamikawa S, Hirohata S, Mizutani A, Abe K, Seno M, Oohashi T, Ninomiya Y

    Acta Med Okayama   69 ( 3 )   145 - 153   2015年6月

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  • ADAMTSによるバーシカン分解と腫瘍内血管新生の関連

    浅野 恵一, 稲垣 純子, 障子 友理, Hofmann Matthias, 大月 孝志, 廣畑 聡, 大橋 俊孝

    日本結合組織学会学術大会プログラム・抄録集   47回   114 - 114   2015年5月

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    記述言語:日本語   出版者・発行元:日本結合組織学会  

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  • メカニカルストレスが軟骨様細胞の細胞外マトリックス及びマトリックス分解酵素のmRNA発現へ示す効果の検討

    大月 孝志, 金道 幸子, 長谷川 みさ, 平田 彩, 川地 輝幸, 浅野 恵一, 稲垣 純子, 障子 友理, 熊岸 加苗, 西田 圭一郎, 大橋 俊孝, 廣畑 聡

    日本結合組織学会学術大会プログラム・抄録集   47回   134 - 134   2015年5月

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    記述言語:日本語   出版者・発行元:日本結合組織学会  

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  • 関節軟骨造影剤を用いた関節軟骨プロテオグリカンの評価

    大橋 俊孝, 加来田 博貴, 芳谷 学, 山田 翔也, 大月 孝志, 廣畑 聡, 二宮 善文, 西田 圭一郎

    日本結合組織学会学術大会プログラム・抄録集   47回   97 - 97   2015年5月

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  • 敗血症性ショック患者における動脈圧波形変化の解析による血管状態の推定

    平山隆浩, 北脇知己, 佐藤圭路, 湯本哲也, 林久美子, 鵜川豊世武, 廣畑 聡 氏家良人

    ICUとCCU   39 ( 12 )   747 - 751   2015年

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  • Early eicosapentaenoic acid treatment after percutaneous coronary intervention reduces acute inflammatory responses and ventricular arrhythmias in patients with acute myocardial infarction: A randomized, controlled study

    Masayuki Doi, Kazumasa Nosaka, Toru Miyoshi, Mutsumi Iwamoto, Masahito Kajiya, Keisuke Okawa, Rie Nakayama, Wataru Takagi, Ko Takeda, Satoshi Hirohata, Hiroshi Ito

    INTERNATIONAL JOURNAL OF CARDIOLOGY   176 ( 3 )   577 - 582   2014年10月

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    Objective: We examined whether early loading of eicosapenlaenoic acid (EPA) reduces clinical adverse events by 1 month, accompanied by a decrease in C-reactive protein (CRP) values in patients with acute myocardial infarction (MI).
    Background: Acute MI triggers an inflammatory reaction, which plays an important role in myocardial injury. EPA could attenuate the inflammatory response.
    Methods: This prospective, open-label, blinded endpoint, randomized trial consisted of 115 patients with acute MI. They were randomly assigned to the EPA group (57 patients) and the control group (58 patients). After percutaneous coronary intervention (PCI), 1800 mg/day of EPA was initiated within 24 h.The primary endpoint was composite events, including cardiac death, stroke, re-infarction, ventricular arrhythmias, and paroxysmal atrial fibrillation within 1 month.
    Results: Administration of EPA significantly reduced the primary endpoint within 1 month (10.5 vs 29.3%, p = 0.01), especially the incidence of ventricular arrhythmias (7.0 vs 20.6%, p = 0.03). Peak CRP values after PCI in the EPA group were significantly lower than those in the control group (median [interquartile range], 8.2 [5.6-10.21 mg/dl vs 9.7 [7.6-13.91 mg/dl p &lt; 0.01). Logistic regression analysis showed that EPA use was an independent factor related to ventricular arrhythmia until 1 month, with an odds ratio of 0.29 (95% confidence interval, 0.09 to 0.96, p = 0.04).
    Conclusions: Early EPA treatment after PCI in the acute stage of MI reduces the incidence of ventricular arrhythmias, and lowers CRP values. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.ijcard.2014.08.055

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  • ヒアルロン酸短期投与によるラット変形性関節症モデルの関節軟骨保護効果の検討

    大月 孝志, 廣畑 聡, 障子 友理, 浅野 恵一, 平田 彩, 川地 輝幸, 稲垣 純子, 熊岸 加苗, 西田 圭一郎, 二宮 善文

    日本結合組織学会学術大会・マトリックス研究会大会合同学術集会プログラム・抄録集   46回・61回   107 - 107   2014年6月

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  • 新規X線造影剤による変形性膝関節症ラット関節軟骨の高解像度マイクロCT造影

    大橋 俊孝, 加来田 博貴, 芳谷 学, 大月 孝志, 大野 充昭, 山田 翔也, 前原 亜美, 廣畑 聡, 西田 圭一郎, 窪木 拓男, 二宮 善文

    日本結合組織学会学術大会・マトリックス研究会大会合同学術集会プログラム・抄録集   46回・61回   106 - 106   2014年6月

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  • 胎生期ADAMTS1ノックアウトマウスの解析

    楠 絵里子, 稲垣 純子, 大月 孝志, 川地 輝幸, 平田 彩, 浅野 恵一, マティアス・ホフマン, 二宮 善文, 廣畑 聡

    日本結合組織学会学術大会・マトリックス研究会大会合同学術集会プログラム・抄録集   46回・61回   76 - 76   2014年6月

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  • ADAMTS1はVEGFCと結合してリンパ管新生を抑制する

    稲垣 純子, 高橋 克之, 小川 弘子, 浅野 恵一, Hatipoglu Omer Faruk, Cile Mehmet Zeynel, 小比賀 真就, 大月 孝志, Hofmann Matthias, 草地 省蔵, 二宮 善文, 廣畑 聡

    日本結合組織学会学術大会・マトリックス研究会大会合同学術集会プログラム・抄録集   46回・61回   137 - 137   2014年6月

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  • 担がんマウスモデルにおけるバーシカン分解の解析

    浅野 恵一, 稲垣 純子, マティアス・ホフマン, 川地 輝幸, 平田 彩, 大月 孝志, 二宮 善文, 廣畑 聡

    日本結合組織学会学術大会・マトリックス研究会大会合同学術集会プログラム・抄録集   46回・61回   89 - 89   2014年6月

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  • ADAMTS1 inhibits lymphangiogenesis by attenuating phosphorylation of the lymphatic endothelial cell-specific VEGF receptor

    Junko Inagaki, Katsuyuki Takahashi, Hiroko Ogawa, Keiichi Asano, Omer Faruk Hatipoglu, Mehmet Zeynel Cilek, Masanari Obika, Takashi Ohtsuki, Matthias Hofmann, Shozo Kusachi, Yoshifumi Ninomiya, Satoshi Hirohata

    EXPERIMENTAL CELL RESEARCH   323 ( 2 )   263 - 275   2014年5月

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    記述言語:英語   出版者・発行元:ELSEVIER INC  

    Angiogenesis and lymphangiogenesis play roles in malignant tumor progression, dissemination, and metastasis. ADAMTS1, a member of the matrix metalloproteinase family, is known to inhibit angiogenesis. Recombinant ADAMTS1 was shown to strongly inhibit angiogenesis. We investigated whether ADAMTSI inhibited lymphangiogenesis in the present study. We examined cell proliferation and cell migration in normal human dermal lymphatic microvascular endothelial cells (HMVEC-dLy) transduced with or without adenoviral human ADAMTS1 gene therapy. We then examined the VEGFC/ VEGFR3 signal transduction pathway in ADAMTS1-transduced HMVEC-dLy. Cell proliferation and tube formation in Matrigel were significantly lower with transduced ADAMTS1 than with control (non-transduced HMVEC-dLy). The phosphorylation of VEGFR3 was also attenuated by ADAMTS1 gene therapy in HMVEC-dLy. Immunoprecipitation assays revealed that ADAMTS1 formed a complex with VEGFC Our results demonstrated that ADAMTS1 inhibited lymphangiogenesis in vitro. The data highlight the new function of ADAMTS1 in the regulation of lymphangiogeneSis and the therapeutic potential of ADAMTSI in cancer therapy. (c) 2014 Elsevier Inc. All rights reserved.

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  • Low serum level of secreted frizzled-related protein 5, an anti-inflammatory adipokine, is associated with coronary artery disease

    Toru Miyoshi, Masayuki Doi, Shinichi Usui, Mutsumi Iwamoto, Masahito Kajiya, Ko Takeda, Kazumasa Nosaka, Rie Nakayama, Keisuke Okawa, Wataru Takagi, Kazufumi Nakamura, Satoshi Hirohata, Hiroshi Ito

    ATHEROSCLEROSIS   233 ( 2 )   454 - 459   2014年4月

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    Objective: Secreted frizzled-related protein 5 (SFRP5) is an anti-inflammatory adipokine that is associated with insulin resistance in animals. To extend these observations to humans, we investigated the association of serum SFRP5 levels in subjects with and without coronary artery disease (CAD).
    Methods: Subjects (n = 185, 68 + 11 years, 79% male) suspected of having CAD were enrolled in the study and were divided into two groups, CAD and non-CAD subjects, according to the results of their coronary angiographies. Serum SFRP5 levels of the subjects were measured by an enzyme-linked immunosorbent assay.
    Results: The serum SFRP5 levels in the subjects with CAD were significantly lower than those in the non-CAD subjects (median [interquartile range]: 47.7 [26.6] vs. 52.4 [29.6] ng/mL, respectively; p = 0.02). The serum SFRP5 levels significantly correlated with body mass index, the homeostasis model of assessment of insulin resistance, adiponectin levels, and CAD severity. Multivariate logistic regression analysis revealed that a decreased serum SFRP5 level (log transformed) was independently associated with CAD for all subjects (adjusted odds ratio, 0.36; 95% confidence interval, 0.14-0.94; p = 0.03).
    Conclusion: Serum SFRP5 levels are significantly associated with CAD in humans, suggesting that low SFRP5 levels may contribute to CAD. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

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  • ADAMTS4 and ADAMTS5 Knockout Mice Are Protected from Versican but Not Aggrecan or Brevican Proteolysis during Spinal Cord Injury 国際誌

    Kadir Demircan, Vehap Topcu, Tomoyuki Takigawa, Sumeyya Akyol, Tomoko Yonezawa, Gulfer Ozturk, Veli Ugurcu, Rukiye Hasgul, M. Ramazan Yigitoglu, Omer Akyol, Daniel R. McCulloch, Satoshi Hirohata

    BIOMED RESEARCH INTERNATIONAL   2014 ( 2014 )   693746 - 693746   2014年

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    記述言語:英語   出版者・発行元:HINDAWI PUBLISHING CORPORATION  

    The chondroitin sulfate proteoglycans (CSPGs) aggrecan, versican, and brevican are large aggregating extracellular matrix molecules that inhibit axonal growth of the mature central nervous system (CNS). ADAMTS proteoglycanases, including ADAMTS4 and ADAMTS5, degrade CSPGs, representing potential targets for ameliorating axonal growth-inhibition by CSPG accumulation after CNS injury. We investigated the proteolysis of CSPGs in mice homozygous for Adamts4 or Adamts5 null alleles after spinal cord injury (SCI). ADAMTS-derived 50-60 kDa aggrecan and 50 kDa brevican fragments were observed in Adamts4-/-, Adamts5-/-, and wt mice but not in the sham-operated group. By contrast Adamts4-/- and Adamts5-/- mice were both protected from versican proteolysis with an ADAMTS-generated 70 kDa versican fragment predominately observed in WT mice. ADAMTS1, ADAMTS9, and ADAMTS15 were detected by Western blot in Adamts4-/- mice' spinal cords after SCI. Immunohistochemistry showed astrocyte accumulation at the injury site. These data indicate that aggrecan and brevican proteolysis is compensated in Adamts4-/- or Adamts5-/- mice by ADAMTS proteoglycanase family members but a threshold of versican proteolysis is sensitive to the loss of a single ADAMTS proteoglycanase during SCI. We show robust ADAMTS activity after SCI and exemplify the requirement for collective proteolysis for effective CSPG clearance during SCI.

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  • New Estimation Method of Total Creatine Phosphokinase Release in Early Stage in Acute Myocardial Infarction

    Kitawaki T, Oka H, Usui S, Hirohata S, Kusachi S

    International Journal of Cardiovascular and Cerebrovascular Disease   2 ( 2 )   18 - 27   2014年

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  • Serum adipocyte fatty acid-binding protein is independently associated with complex coronary lesions in patients with stable coronary artery disease

    Masahito Kajiya, Toru Miyoshi, Masayuki Doi, Shinichi Usui, Mutsumi Iwamoto, Ko Takeda, Kazumasa Nosaka, Rie Nakayama, Satoshi Hirohata, Shozo Kusachi, Kazufumi Nakamura, Hiroshi Ito

    HEART AND VESSELS   28 ( 6 )   696 - 703   2013年11月

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    記述言語:英語   出版者・発行元:SPRINGER  

    The association between circulating adipocyte fatty acid-binding protein (A-FABP) levels and coronary artery disease (CAD) is reported. We assessed whether plasma A-FABP levels are associated with angiographic coronary lesion morphology in patients with stable CAD. Serum A-FABP levels were analyzed in 115 patients with stable CAD (mean age 69 +/- 10 years; 80 % men). These patients were angiographically studied and divided into two groups: simple lesions (n = 34) and complex lesions (n = 81). We also compared 50 age- and gender-matched controls with no evidence of CAD. Serum A-FABP levels in patients with stable CAD were significantly higher than those in controls. In patients with stable CAD, serum A-FABP levels were significantly higher in patients with complex lesions than in those with simple lesions: median (25th-75th percentile), 23.4 (17.7-30.8) vs 18.2 (12.2-24.7) ng/ml, P &lt; 0.01. Serum A-FABP levels were also significantly associated with angiographic scores of extent of coronary lesion (r = 0.21, P = 0.02). Multiple logistic analysis that included dyslipidemia, statin therapy, and extent score demonstrated that serum A-FABP was independently associated with complex lesions. The multiple adjusted odds ratio for a complex lesion with a serum A-FABP level (per doubling) was 2.38 (95 % confidence interval, 1.03-6.41; P = 0.03). High serum A-FABP levels were significantly associated with complex coronary lesions in patients with stable CAD, suggesting that high A-FABP levels may be involved in coronary plaque vulnerability.

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  • Augmentation of ADAMTS9 gene expression by IL-1β is reversed by NFκB and MAPK inhibitors, but not PI3 kinase inhibitors 国際誌

    Uysal S, Unal ZN, Erdoğan S, Akyol S, Ramazan Yiğitoğlu M, Hirohata S, Işık B, Demircan K

    Cell Biochemistry and Function   31 ( 7 )   539 - 544   2013年10月

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  • Vascular Endothelial Growth Factor C-Induced Lymphangiogenesis Decreases Tumor Interstitial Fluid Pressure and Tumor Growth

    Matthias Hofmann, Ralph Pflanzer, Nadja Nicole Zoeller, August Bernd, Roland Kaufmann, Diamant Thaci, Juergen Bereiter-Hahn, Satoshi Hirohata, Stefan Kippenberger

    TRANSLATIONAL ONCOLOGY   6 ( 4 )   398 - 404   2013年8月

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    記述言語:英語   出版者・発行元:NEOPLASIA PRESS  

    Characteristically, most solid tumors exhibit an increased tumor interstitial fluid pressure (TIFP) that directly contributes to the lowered uptake of macromolecular therapeutics into the tumor interstitium. Abnormalities in the tumor-associated lymph vessels are a central brick in the development and prolonged sustaining of an increased TIFP. In the current study, vascular endothelial growth factor C (VEGF-C) was used to enhance tumor-associated lymphangiogenesis as a new mechanism to actively reduce the TIFP by increased lymphatic drainage of the tumor tissue. Human A431 epidermoid vulva carcinoma cells were inoculated in NMRI nu/nu mice to generate a xenograft mouse model. Seven days after tumor cell injection, VEGF-C was peritumorally injected to induce lymphangiogenesis. Tumor growth and TIFP was lowered significantly over time in VEGF-C-treated tumors in comparison to control or VEGF-A-treated animals. These data demonstrate for the first time that actively induced lymphangiogenesis can lower the TIFP in a xenograft tumor model and apparently reduce tumor growth. This model represents a novel approach to modulate biomechanical properties of the tumor interstitium enabling a lowering of TIFP in vivo.

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  • Adaptive-servo ventilation combined with deep sedation is an effective strategy during pulmonary vein isolation 国際誌

    Takashi Murakami, Hirosuke Yamaji, Kenji Numa, Hiroshi Kawamura, Masaaki Murakami, Shunichi Higashiya, Shigeshi Kamikawa, Kazuyoshi Hina, Satoshi Hirohata, Shozo Kusachi

    Europace   15 ( 7 )   951 - 956   2013年7月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS  

    AimsPulmonary vein isolation (PVI) by catheter ablation for atrial fibrillation (AF) requires suppression of patient restlessness by sufficient sedation in addition to maintaining stable respiration. We applied adaptive-servo ventilation (ASV) and examined the effects of ASV combined with deep propofol sedation on PVI using a NavX.Methods and resultsWe analysed 75 paroxysmal AF (PAF) patients (62 ± 11 years
    53 men and 22 women) who underwent PVI for treatment of PAF using an ASV system combined with deep sedation (ASV group). Control patients included 75 consecutive PAF patients (62 ± 11 years
    51 men and 24 women) who underwent PVI just before introduction of the ASV system. Deep sedation was defined as a Ramsay sedation score of 6. The ASV group had a lower frequency of restless body movements compared with the control group during PVI (1.5 ± 0.7 vs. 7.8 ± 1.4 times, P &lt
    0.01). The frequency of respiratory compensation and EnGuide alignment of catheter position by the NavX was lower in the ASV (4.2 ± 3.3 and 8.8 ± 7.1 times) than control group (7.1 ± 5.1 and 15.2 ± 10.0 times, P &lt
    0.05 and &lt
    0.01, respectively). Consequently, significantly lower total electrical energy supply (48.7 ± 6.0 KJ) was required in the ASV than control group (64.5 ± 24.9 KJ, P &lt
    0.01). Further, significantly shorter fluoroscopy and procedural times were observed in the ASV (28 ± 5 and 109 ± 25 min) than the control group (33 ± 6 and 141 ± 38 min, respectively, P &lt
    0.01) and the AF recurrence rate was significantly lower in the ASV than the control group (12 vs. 25%, P &lt
    0.01).ConclusionASV combined with deep sedation is an effective strategy during PVI using the NavX in patients with PAF. © 2013 The Author.

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  • ADAMTS1, ADAMTS5, ADAMTS9 and aggrecanase-generated proteoglycan fragments are induced following spinal cord injury in mouse

    Kadir Demircan, Tomoko Yonezawa, Tomoyuki Takigawa, Vehap Topcu, Serpil Erdogan, Fatma Ucar, Ferah Armutcu, M. Ramazan Yigitoglu, Yoshifumi Ninomiya, Satoshi Hirohata

    NEUROSCIENCE LETTERS   544   25 - 30   2013年6月

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) proteinases are involved in a variety of biological processes such as angiogenesis, cancer and arthritis. ADAMTSs appears to be responsible for the cleavage of proteoglycans in several tissues including brain and cartilage. Chondroitin sulfate proteoglycans (CSPGs) maintains the integrity of the brain extracellular matrix and major inhibitory contributors for glial scar and neural plasticity. The activity of aggrecanases in the central nervous system (CNS)has been reported. ADAMTSs are an enzyme degrading CSPGs in the brain. However, there is a little knowledge regarding ADAMTSs in the CNS. We investigated the expression levels of ADAMTSs mRNAs by RT-PCR after spinal cord injury in mouse. Transcripts encoding 4 of the 19 known ADAMTSs were evaluated in the mouse spinal cord following injury. ADAMTS1, -5 and -9 expression levels were found to be upregulated. No change was observed in ADAMTS4 expression. By means of immunohistochemistry, ADAMTSs were detected in the astrocytes implying its cellular source in SCI. Western blot analyses indicated that aggrecanase-generated proteoglycan fragments are produced after SCI. (c) 2013 Elsevier Ireland Ltd. All rights reserved.

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  • ヒアルロン酸(HA)分子量と関節軟骨保護効果の解析(in vivo & in vitro)

    大月 孝志, 廣畑 聡, 浅野 恵一, 楠 絵理子, 稲垣 純子, 西田 圭一郎, 二宮 善文

    日本結合組織学会学術大会・マトリックス研究会大会合同学術集会プログラム・抄録集   45回・60回   74 - 74   2013年6月

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    記述言語:日本語   出版者・発行元:日本結合組織学会・マトリックス研究会  

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  • Eosinophil cationic protein enhances stabilization of β-catenin during cardiomyocyte differentiation in P19CL6 embryonal carcinoma cells 国際誌

    Jin G, Mizutani A, Fukuda T, Otani T, Yan T, Prieto Vila M, Murakami H, Kudoh T, Hirohata S, Kasai T, Salomon DS, Seno M

    Molecular Biology Reports   40 ( 4 )   3165 - 3171   2013年4月

  • Reduced Diurnal Variation of Heart Rate is Associated With Increased Plasma B-Type Natriuretic Peptide Level in Patients With Atrial Fibrillation 国際誌

    Kamikawa S, Miyoshi T, Doi M, Orita N, Sangawa M, Nakatsu T, Noguchi Y, Hirohata S, Kusachi S, Nakamura K, Ito H

    Clinical Cardiology   36 ( 7 )   394 - 400   2013年

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  • Usefulness of Dabigatran Etexilate as Periprocedural Anticoagulation Therapy for Atrial Fibrillation Ablation 国際誌

    Hirosuke Yamaji, Takashi Murakami, Kazuyoshi Hina, Shunichi Higashiya, Hiroshi Kawamura, Masaaki Murakami, Shigeshi Kamikawa, Satoshi Hirohata, Shozo Kusachi

    CLINICAL DRUG INVESTIGATION   33 ( 6 )   409 - 418   2013年

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    記述言語:英語   出版者・発行元:ADIS INT LTD  

    The usefulness of dabigatran etexilate for the prevention of stroke in patients with atrial fibrillation (AF) has been reported.
    In this study the efficacy and safety of dabigatran etexilate for anticoagulation for AF ablation were examined.
    Patients were divided into three groups: Group 1, interrupted warfarin bridged by heparin between pre- and post-ablation; Group 2, continuous warfarin therapy; and Group 3, dabigatran etexilate therapy. Anticoagulation therapy with warfarin or dabigatran etexilate was performed from 30 days before to at least 90 days after AF ablation. Dabigatran etexilate was administered at 110 or 150 mg twice daily, depending on renal function and age.
    Patients' clinical characteristics, associated disorders, echocardiographic parameters and arrhythmia status were not different among the three groups. Procedural parameters such as procedural time and radiofrequency energy supply were also not different among the three groups. The dabigatran etexilate group and the warfarin groups had no embolic complications (stroke, cerebral transient ischaemic attack, deep venous thrombosis or pulmonary embolism). No pericardial tamponade was observed in the dabigatran etexilate group, while two patients in each of Group 1 (2/194, 1.0 %) and Group 2 (2/203, 0.98 %) developed cardiac tamponade, though the differences were not significant. Pericardial effusion and groin haematoma were observed in one patient each (1/105, 0.9 %) in the dabigatran etexilate group, and the incidences were not different from the warfarin group (Group 1: 4/194, 2.1 % and 2/194, 1.0 %; Group 2: 3/203, 1.5 % and 2/203, 1.0 %, respectively). As a whole, the safety outcomes did not differ among the three groups.
    Dabigatran etexilate is an effective and safe anticoagulation therapy for AF ablation. Thus, dabigatran etexilate appears to be useful as an alternative anticoagulant therapy to warfarin for AF ablation.

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  • ADAMTSの機能

    廣畑 聡

    血管新生研究の最先端   208 - 216   2013年

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  • リンパ管内皮細胞に対するADAMTS1の作用とシグナル伝達

    稲垣 純子, 高橋 克之, 小川 弘子, Hatipoglu Omer F, Zeynel Cilek Mehmet, 小比賀 真就, 廣畑 聡, 二宮 善文

    日本生化学会大会プログラム・講演要旨集   85回   2P - 832   2012年12月

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  • Cyclic tensile strain inhibits interleukin-1 beta and tumor ncerosis factor-alpha-induced aggrecanase in human chondrosarcoma cell line OUMS-27 by stretch-activated channles

    Takashi Ohtsuki, Keiichiro Nishida, Satoshi Hirohata, Yoshifumi Ninomiya

    GLYCOBIOLOGY   22 ( 11 )   1582 - 1583   2012年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:OXFORD UNIV PRESS INC  

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  • The tumor growth inhibitory effect of ADAMTS1 is accompanied by the inhibition of tumor angiogenesis

    Satoshi Hirohata, Takashi Ohtsuki, Masanari Obika, Hiroko Ogawa, Shozo Kusachi, Yoshifumi Ninomiya

    GLYCOBIOLOGY   22 ( 11 )   1559 - 1559   2012年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:OXFORD UNIV PRESS INC  

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  • Tumor growth inhibitory effect of ADAMTS1 is accompanied by the inhibition of tumor angiogenesis. 国際誌

    Masanari Obika, Hiroko Ogawa, Katsuyuki Takahashi, Jiayi Li, Omer Faruk Hatipoglu, Mehmet Zeynel Cilek, Toru Miyoshi, Junko Inagaki, Takashi Ohtsuki, Shozo Kusachi, Yoshifumi Ninomiya, Satoshi Hirohata

    Cancer science   103 ( 10 )   1889 - 97   2012年10月

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    記述言語:英語  

    Angiogenesis plays an important role in tumor progression. Several reports have demonstrated that a disintegrin and metalloproteinase with thrombospondin motifs1 (ADAMTS1) inhibited angiogenesis via multiple mechanisms. The aim of this study was to investigate the effect of ADAMTS1 on endothelial cells in vitro and on tumor growth with regard to angiogenesis in vivo. We examined the effects of the transfection of ADAMTS1 using two constructs, full-length ADAMTS1 (full ADAMTS1) and catalytic domain-deleted ADAMTS1 (delta ADAMTS1). Transfection of both the full ADAMTS1 and delta ADAMTS1 gene constructs demonstrated the secretion of tagged-ADAMTS1 protein into the conditioned medium, so we examined the effects of ADAMTS1-containing conditioned medium on endothelial cells. Both types of conditioned media inhibited endothelial tube formation, and this effect was completely abolished after immunoprecipitation of the secreted protein from the medium. Both types of conditioned media also inhibited endothelial cell migration and proliferation. We then examined the impact of ADAMTS1 on endothelial cell apoptosis. Both conditioned media increased the number of Annexin V-positive endothelial cells and caspase-3 activity and this effect was attenuated when z-vad was added. These results indicated that ADAMTS1 induced endothelial cell apoptosis. We next examined the effects of ADAMTS1 gene transfer into tumor-bearing mice. Both full ADAMTS1 and delta ADAMTS1 significantly inhibited the subcutaneous tumor growth. Collectively, our results demonstrated that ADAMTS1 gene transfer inhibited angiogenesis in vitro and in vivo, likely as a result of the induction of endothelial cell apoptosis by ADAMTS1 that occurs independent of the protease activity.

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  • Eosinophil cationic protein enhances cardiomyocyte differentiation of P19CL6 embryonal carcinoma cells by stimulating the FGF receptor signaling pathway 国際誌

    Guoliang Jin, Akifumi Mizutani, Takayuki Fukuda, Ling Chen, Keisuke Nakanishi, Ting Yan, Takayuki Kudoh, Satoshi Hirohata, Tomonari Kasai, Hiroshi Murakami, David S. Salomon, Masaharu Seno

    GROWTH FACTORS   30 ( 5 )   344 - 355   2012年10月

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    記述言語:英語   出版者・発行元:INFORMA HEALTHCARE  

    We investigated the functional role of eosinophil cationic protein (ECP) in regulating cardiomyogenesis using mouse P19CL6 embryonic carcinoma cells. ECP was confirmed to accelerate the cardiomyocyte differentiation of P19CL6 cells by enhancing the rate and area size of beating of cardiomyocyte and by facilitating the expression of cardiomyocyte-specific genes, such as GATA4 and alpha-MHC. Since cardiomyocyte differentiation in vivo is considered to follow mesoderm induction, the induction of Brachyury, a marker of mesoderm, was assessed. Brachyury expression was found to be enhanced after the addition of ECP. This enhancement was due to the stimulation of extracellular signal-regulated kinase (ERK) 1/2 phosphorylation by ECP. In this context, treatment with SU5402, an inhibitor of fibroblast growth factor (FGF) receptor 1, suppressed Brachyury expression, phosphorylation of ERK1/2, and cardiomyocyte differentiation induced by ECP. We concluded that ECP might induce mesoderm differentiation through FGF signaling pathway and enhance subsequent cardiomyocyte differentiation in concert with dimethyl sulfoxide in P19CL6 cells. ECP may be a novel factor for cardiomyocyte differentiation, which should be very useful to prepare adequate numbers of cardiomyocytes for therapeutic cell transplantation.

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  • ADAMTS1ノックアウトマウスの解析

    廣畑 聡, ハティポール・オメル・ファルク, 楠 絵理子, チレッキ・メフメット・ゼイネル, 大月 孝志, 稲垣 純子, 草地 省蔵, 二宮 善文

    日本結合組織学会学術大会・マトリックス研究会大会合同学術集会プログラム・抄録集   44回・59回   57 - 57   2012年6月

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  • Impact of MDA-LDL/LDL-C and AA/EPA ratio to plaque vulnerability in patients with stable angina pectoris

    Hiroaki Otsuka, Masayuki Ueeda, Takuro Masuda, Yasunori Arai, Daisuke Yamada, Nobuhiko Ohnishi, Atsushi Takaishi, Satoshi Hirohata, Shozo Kusachi, Hiroshi Ito

    CIRCULATION   125 ( 19 )   E697 - E697   2012年5月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Elevated serum adipocyte fatty acid-binding protein concentrations are independently associated with renal dysfunction in patients with stable angina pectoris 国際誌

    Mutsumi Iwamoto, Toru Miyoshi, Masayuki Doi, Ko Takeda, Masahito Kajiya, Kazumasa Nosaka, Rie Nakayama, Satoshi Hirohata, Shinichi Usui, Shozo Kusachi, Kosuke Sakane, Kazuhfumi Nakamura, Hiroshi Ito

    CARDIOVASCULAR DIABETOLOGY   11 ( 26 )   26 - 26   2012年3月

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    記述言語:英語   出版者・発行元:BIOMED CENTRAL LTD  

    Background: Chronic kidney disease (CKD) is associated with cardiovascular events. Adipocyte fatty acid-binding protein (A-FABP) plays an important role in atherosclerosis. We investigated whether plasma A-FABP is involved in renal function in patients with stable angina pectoris.
    Methods: A total of 221 patients with significant coronary artery stenosis were enrolled after coronary angiography. CKD was defined as an estimated glomerular filtration rate (eGFR) &lt; 60 ml/min/1.73 m(2). The severity of coronary stenosis was assessed using a modified Gensini score and coronary angiography. Serum A-FABP levels were determined by enzyme-linked immunosorbent assay.
    Results: Serum A-FABP levels were significantly correlated with both eGFR (r = -0.41, p &lt; 0.01) and the severity of coronary artery stenosis (r = 0.16, p = 0.02), and these relationships remained significant after adjusting for confounding factors. The prevalence of CKD and multi-vessel disease was significantly higher among patients with serum A-FABP levels above the median value of 20.3 ng/ml than among patients with serum A-FABP levels below the median value (57% vs. 27%, p &lt; 0.01 and 64% vs. 48%, p = 0.02, respectively). Multivariate analysis revealed that the presence of three-vessel disease in comparison with single-vessel disease was independently associated with the higher A-FABP (per doubling) (odds ratio; 2.26, 95% confidential interval; 1.28-3.98, p &lt; 0.01) and tended to be associated with the lower eGFR (p = 0.06).
    Conclusion: Serum A-FABP may have a significant role in the interplay between renal dysfunction and coronary atherosclerosis.

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  • Sufficient pulmonary vein image quality of non-enhanced multi-detector row computed tomography for pulmonary vein isolation by catheter ablation 国際誌

    Hirosuke Yamaji, Kazuyoshi Hina, Hiroshi Kawamura, Takashi Murakami, Masaaki Murakami, Satoshi Hirohata, Natsuki Ohmaru, Shozo Kusachi

    EUROPACE   14 ( 1 )   52 - 59   2012年1月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS  

    Aims We evaluated the quality of non-enhanced multi-detector row computed tomography (MDCT) images of the pulmonary vein (PV) and the clinical results of catheter ablation to isolate the PV for treatment of atrial fibrillation (AF) without the use of contrast medium in patients with chronic kidney disease (CKD).
    Methods and results We compared PV images quantitatively and qualitatively between non-enhanced and enhanced images (n = 50). Procedural parameters and clinical outcomes were compared between catheter ablation for AF referring solely to non-enhanced MDCT in CKD patients (n = 20) and using enhanced MDCT images integrated with electroanatomic mapping in non-CKD patients (n = 30). In gross anatomy, complete agreement was obtained between non-enhanced and enhanced MDCT images. Bland-Altman plots and cumulative coefficient variation showed good agreement in PV diameter determination between non-enhanced and enhanced MDCT images. There were no statistically significant differences in procedural or fluoroscopic times between PV isolation only referring to non-enhanced MDCT images and that using enhanced MDCT images integrated with electroanatomic mapping. Similarly, the ablation success rate and AF-free status at 3 months after PV isolation did not differ between PV isolation referring only to non-enhanced MDCT images and that using an electroanatomic integration system. No complications occurred in PV isolation with or without enhanced MDCT.
    Conclusions Non-enhanced MDCT provides adequate PV image quality both quantitatively and qualitatively. The present study suggests that catheter ablation referring solely to non-enhanced MDCT images for AF could be performed with clinically acceptable results. These findings warrant further studies involving a much larger number of patients to confirm the present results.

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  • Four-year clinical outcomes of the OLIVUS-Ex (impact of Olmesartan on progression of coronary atherosclerosis: Evaluation by intravascular ultrasound) extension trial 国際誌

    Atsushi Hirohata, Keizo Yamamoto, Toru Miyoshi, Kunihiko Hatanaka, Satoshi Hirohata, Hitoshi Yamawaki, Issei Komatsubara, Eiki Hirose, Yuhei Kobayashi, Keisuke Ohkawa, Minako Ohara, Hiroya Takafuji, Fumihiko Sano, Yuko Toyama, Shozo Kusachi, Tohru Ohe, Hiroshi Ito

    ATHEROSCLEROSIS   220 ( 1 )   134 - 138   2012年1月

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    Background: The previous OLIVUS trial reported a positive role in achieving a lower rate of coronary atheroma progression through the administration of Olmesartan, an angiotension-II receptor blocking agent (ARB), for stable angina pectoris (SAP) patients requiring percutaneous coronary intervention (PCI). However, the benefits between ARB administration on long-term clinical outcomes and serial atheroma changes by IVUS remain unclear. Thus, we examined the 4-year clinical outcomes from OLIVUS according to treatment strategy with Olmesartan.
    Methods: Serial volumetric IVUS examinations (baseline and 14 months) were performed in 247 patients with hypertension and SAP. When these patients underwent PCI for culprit lesions, IVUS was performed in their non-culprit vessels. Patients were randomly assigned to receive 20-40mg of Olmesartan or control, and treated with a combination of beta-blockers, calcium channel blockers, glycemic control agents and/or statins per physician's guidance. Four-year clinical outcomes and annual progression rate of atherosclerosis, assessed by serial IVUS, were compared with major adverse cardio-and cerebrovascular events (MACCE).
    Results: Cumulative event-free survival was significantly higher in the Olmesartan group than in the control group (p = 0.04; log-rank test). By adjusting for validated prognosticators, Olmesartan administration was identified as a good predictor of MACCE (p = 0.041). On the other hand, patients with adverse events (n = 31) had larger annual atheroma progression than the rest of the population (23.8% vs. 2.1%, p &lt; 0.001).
    Conclusions: Olmesartan therapy appears to confer improved long-term clinical outcomes. Atheroma volume changes, assessed by IVUS, seem to be a reliable surrogate for future major adverse cardio-and cerebrovascular events in this study cohort. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.atherosclerosis.2011.10.013

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  • Serum hepatitis B virus DNA before liver transplantation correlates with HBV reinfection rate even under successful low-dose hepatitis B immunoglobulin prophylaxis (共著)

    Yasunaka T, Takaki A, Yagi T, Iwasaki Y, Sadamori H, Koike K, Hirohata S, Tatsukawa M, Kawai D, Shiraha H, Miyake Y, Ikeda F, Kobashi H, Matsuda H, Shinoura S, Yoshida R, Satoh D, Utsumi M, Onishi T, Yamamoto K

    Hepatology International   5 ( 4 )   918 - 926   2011年12月

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  • ADAMTS1 Play Roles In Endothelial Cell Apoptosis

    Satoshi Hirohata, Masanari Obika, Faruk Hatipoglu, Kunihiko Hatanaka, Toru Miyoshi, Hiroko Ogawa, Kaori Sakamoto, Mehmet Z. Cilek, Junko Inagaki, Hiroshi Ito, Shozo Kusachi, Yoshifumi Ninomiya

    CIRCULATION   124 ( 21 )   2011年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Residual Diastolic Cross-Bridge and Decreased Expression of Energy Metabolism Genes in Hypertrophied Rat Hearts Induced by Chronic beta-Adrenergic Stimulation

    Kazufumi Nakamura, Daiji Miura, Juichiro Shimizu, Toru Miyoshi, Hiroko Toyota, Hiroshi Okuyama, Wakako Yoshikawa, Satoshi Akagi, Kunihisa Kohno, Masahi Yoshida, Hiroshi Morita, Satoshi Hirohata, Kengo Kusano, Tatsuhito Matsuo, Naoto Yagi, Hirhoshi Ito

    CIRCULATION   124 ( 21 )   2011年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • ADAMTS1のin vitroでのリンパ管新生阻害効果

    稲垣 純子, 高橋 克之, 小川 弘子, Hatipoglu Omer F, Cilek Mehmet Zeynel, 小比賀 真就, 米澤 朋子, 大橋 俊孝, 廣畑 聡, 二宮 善文

    日本生化学会大会プログラム・講演要旨集   84回   2P - 0343   2011年9月

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    記述言語:日本語   出版者・発行元:(公社)日本生化学会  

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  • Olmesartan reduces arterial stiffness and serum adipocyte fatty acid-binding protein in hypertensive patients

    Toru Miyoshi, Masayuki Doi, Satoshi Hirohata, Shigeshi Kamikawa, Shinichi Usui, Hiroko Ogawa, Kosuke Sakane, Reishi Izumi, Yoshifumi Ninomiya, Shozo Kusachi

    HEART AND VESSELS   26 ( 4 )   408 - 413   2011年7月

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    記述言語:英語   出版者・発行元:SPRINGER  

    Adipocyte fatty acid binding protein (A-FABP) has been reported to be involved in insulin resistance, lipid metabolism, and atherosclerosis; however, little is known about the effect of medication on the change in circulating A-FABP in human subjects. We evaluated the effects of angiotensin II type 1 receptor blocker (ARB) on arterial stiffness and its association with serum A-FABP in patients with hypertension. Thirty patients newly diagnosed with essential hypertension were treated with olmesartan (20 mg/day), an ARB, for 6 months. Serum levels of A-FABP and high-sensitivity C-reactive protein (hsCRP) were examined and the cardio-ankle vascular index (CAVI), which is a marker of arterial stiffness, was also determined. Serum A-FABP at baseline was significantly correlated with the body mass index (r = 0.45, P = 0.01), homeostasis model assessment as a marker of insulin resistance (r = 0.53, P &lt; 0.01), and systolic blood pressure (r = 0.37, P = 0.047), and tended to be correlated with low-density lipoprotein cholesterol, triglyceride, and CAVI. Olmesartan treatment resulted in a significant decrease in CAVI, serum A-FABP levels, and hsCRP, besides a significant reduction of blood pressure. Multiple regression analysis revealed that the change in CAVI was independently correlated with the change in serum A-FABP. Olmesartan ameliorated arterial stiffness in patients with hypertension, which may be involved in the reduction of serum A-FABP.

    DOI: 10.1007/s00380-010-0060-x

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  • ADAMTS1は血管新生を阻害しアポトーシスを抑制する

    廣畑 聡, 小比賀 真就, オメル・ファルク・ハティポール, 小川 弘子, メフメット・ゼェイネル・チレッキ, 稲垣 純子, 大月 孝志, 石井 裕子, 幡中 邦彦, 草地 省蔵, 米澤 朋子, 大橋 俊孝, 二宮 善文

    日本結合組織学会学術大会・マトリックス研究会大会合同学術集会プログラム・抄録集   43回・58回   103 - 103   2011年5月

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    記述言語:日本語   出版者・発行元:日本結合組織学会・マトリックス研究会  

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  • ADAMTS1は腫瘍壊死因子刺激下の内皮細胞におけるアポトーシスに関連する

    オメル・ファルク・ハティポール, 小比賀 真就, 廣畑 聡, 小川 弘子, メフメット・ゼェイネル・チレッキ, 稲垣 純子, 大月 孝志, 石井 裕子, 幡中 邦彦, 草地 省蔵, 米澤 朋子, 大橋 俊孝, 二宮 善文

    日本結合組織学会学術大会・マトリックス研究会大会合同学術集会プログラム・抄録集   43回・58回   104 - 104   2011年5月

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    記述言語:日本語   出版者・発行元:日本結合組織学会・マトリックス研究会  

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  • Association of increased plasma adipocyte fatty acid-binding protein with coronary artery disease in non-elderly men 国際誌

    Masayuki Doi, Toru Miyoshi, Satoshi Hirohata, Kazufumi Nakamura, Shinichi Usui, Ko Takeda, Mutsumi Iwamoto, Shozo Kusachi, Kengo Kusano, Hiroshi Ito

    CARDIOVASCULAR DIABETOLOGY   10   44 - 44   2011年5月

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    記述言語:英語   出版者・発行元:BIOMED CENTRAL LTD  

    Background: Adipocyte fatty acid-binding protein (A-FABP) has been reported to play critical roles in the development of atherosclerosis. We investigated whether an increased in plasma A-FABP level can be independently associated with the presence of coronary artery disease (CAD).
    Methods: Two hundred eleven consecutive male patients (mean age: 66 years, range: 33-87 years) were enrolled from inpatients who underwent coronary angiography. Age-matched male subjects (n = 211) having no evidence of CAD served as controls. Plasma A-FABP levels were measured by enzyme-linked immunosorbent assays.
    Results: Plasma A-FABP levels in CAD patients were significantly higher than in control subjects (median [IQR], 20.6 [15.7-27.8] ng/mL vs. 15.1 [11.7-19.9] ng/mL, p &lt; 0.01). Multivariate logistic regression analysis revealed that an increased plasma A-FABP level was independently associated with the presence of CAD in all subjects (adjusted odds ratio: 1.76, 95% confidence interval: 1.14 to 2.70, p = 0.01). Furthermore, sub-analysis based on age showed that this association remained significant in subjects aged &lt; 65 years (adjusted odds ratio: 3.06, 95% confidence interval: 1.34 to 6.98, p &lt; 0.01), but not in subjects aged &gt;= 65 years.
    Conclusions: Increased plasma A-FABP in non-elderly men had a significant association with the presence of CAD, independent of established CAD risk factors.

    DOI: 10.1186/1475-2840-10-44

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  • IMPACT OF INCREASED ARTERIAL STIFFNESS AND WAVE REFLECTION ON THE PREVALENCE OF PAROXYSMAL ATRIAL FIBRILLATION

    Toru Miyoshi, Msayuki Doi, Satoshi Hirohata, Shozo Kusachi, Kazufumi Nakamura, Satoshi Nagase, Kunihisa Kono, Hiroshi Morita, Kengo Kusano, Hiroshi Ito

    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY   57 ( 14 )   E563 - E563   2011年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER SCIENCE INC  

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  • ANTI-INFLAMMATORY EFFECT OF OLMESARTAN ON CORONARY PLAQUE PROGRESSION, FINDING FROM THE IMPACT OF OLMESARTAN ON PROGRESSION OF CORONARY ATHEROSCLEROSIS: EVALUATION BY INTRAVASCULAR ULTRASOUND (OLIVUS) TRIAL

    Toru Miyoshi, Atsushi Hirohata, Shozo Kusachi, Satoshi Hirohata, Kazufumi Nakamura, Hiroshi Morita, Kengo Kusano, Hiroshi Ito

    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY   57 ( 14 )   E604 - E604   2011年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER SCIENCE INC  

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  • Association of serum levels of arachidonic acid and eicosapentaenoic acid with prevalence of major adverse cardiac events after acute myocardial infarction

    Masayuki Ueeda, Takenori Doumei, Yoichi Takaya, Nobuhiko Ohnishi, Atsushi Takaishi, Satoshi Hirohata, Toru Miyoshi, Ryoko Shinohata, Shinichi Usui, Shozo Kusachi

    HEART AND VESSELS   26 ( 2 )   145 - 152   2011年3月

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    記述言語:英語   出版者・発行元:SPRINGER  

    We studied the association of serum levels of arachidonic acid (AA) and eicosapentaenoic acid (EPA) with the prevalence of major adverse cardiac events (MACE) after acute myocardial infarction (AMI). We measured serum AA and EPA on admission in 146 consecutive AMI patients. The primary clinical endpoint was occurrence of MACE, defined as cardiac death, occurrence of heart failure, reinfarction, recurrent angina pectoris, and requirement of coronary intervention. Common logarithmic transformed serum levels of AA (logAA) and EPA (logEPA) were used in the analyses. The optimum cutoff point of each fatty acid used to distribute patients into two groups for Kaplan-Meier analysis was determined by receiver operating characteristic curves analysis. MACE occurred in 40 patients (27.4%). Kaplan-Meier analysis disclosed that the group with a logAA above the cutoff point [145.3 mu g/mL (logAA 2.162)] showed a higher prevalence of MACE than those with a logAA below the cutoff point (P &lt; 0.01). Conversely, the prevalence of MACE was significantly higher in the group with a logEPA below the cutoff point [52.3 mu g/mL (logEPA 1.719)] compared to the group with a logEPA above it (P &lt; 0.01). Similar to logAA, logAA/logEPA showed significant differences in the MACE-free curve between the two groups (cutoff 1.301, P &lt; 0.001). Cox proportional hazards regression analysis suggested that logAA, logEPA, and logAA/logEPA were independently associated with the prevalence of MACE. Although the present study included a limited number of patients with single-time point measurement, the results suggested an association of logAA, logEPA, and logAA/logEPA with the prevalence of MACE after AMI. The present study warrants further studies involving a large number of patients to confirm that the serum levels of these fatty acids and their ratios are predictors of MACE after AMI.

    DOI: 10.1007/s00380-010-0038-8

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  • Regulation of mechanical stress-induced MMP-13 and ADAMTS-5 expression by RUNX-2 transcriptional factor in SW1353 chondrocyte-like cells

    T. Tetsunaga, K. Nishida, T. Furumatsu, K. Naruse, S. Hirohata, A. Yoshida, T. Saito, T. Ozaki

    OSTEOARTHRITIS AND CARTILAGE   19 ( 2 )   222 - 232   2011年2月

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    記述言語:英語   出版者・発行元:W B SAUNDERS CO LTD  

    Objective: To investigate the mechanism of mechanical stress-induced expression and regulation of aggrecanases and examine the role of runt-related transcription factor 2 (RUNX-2) in chondrocyte-like cells.
    Methods: SW1353 cells were seeded onto stretch chambers at a concentration of 5 x 10(4) cells/chamber, and a uni-axial cyclic tensile strain (CTS) (0.5 Hz, 10% stretch) was applied for 30 min. Total RNA was extracted, reverse transcribed, and analyzed by polymerase chain reaction (PCR) and real-time PCR. RUNX-2 overexpression and small interfering RNA (siRNA) targeting RUNX-2 were used to investigate the role of RUNX-2 in CTS-induced gene expression. The involvement of diverse mitogen-activated protein kinase (MAPK) pathways in the activation of RUNX-2, MMP-13 and ADAMTS-5 during CTS was examined by Western blotting.
    Results: CTS induced expression of RUNX-2, MMP-13, ADAMTS-4, -5, and -9. Overexpression of RUNX-2 up-regulated expression of MMP-13 and ADAMTS-5, whereas RUNX-2 siRNA resulted in significant down-regulation of mechanically-induced MMP-13 and ADAMTS-5 expression. CTS induced activation of p38 MAPK, and CTS induction of RUNX-2. MMP-13 and ADAMTS-5 mRNA was down-regulated by the selective p38 MAPK inhibitor SB203580 but not by the p44/42 MAPK inhibitor U0126, or the JNK MAPK inhibitor JNK inhibitor II.
    Conclusions: RUNX-2 might have a role as a key downstream mediator of p38&apos;s ability to regulate mechanical stress-induced MMP-13 and ADAMTS-5 expression. (C) 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.joca.2010.11.004

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  • AHR, a novel acute hypoxia-response sequence, drives reporter gene expression under hypoxia in vitro and in vivo. 国際誌

    Mehmet Zeynel Cilek, Satoshi Hirohata, Omer Faruk Hatipoglu, Hiroko Ogawa, Toru Miyoshi, Junko Inagaki, Takashi Ohtsuki, Hiroshi Harada, Shigeshi Kamikawa, Shozo Kusachi, Yoshifumi Ninomiya

    Cell biology international   35 ( 1 )   1 - 8   2011年1月

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    記述言語:英語  

    ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) is an early immediate gene. We have previously reported that ADAMTS1 was strongly induced by hypoxia. In this study, we investigated whether ADAMTS1 promoter-driven reporter signal is detectable by acute hypoxia. We constructed the GFP (green fluorescent protein) expression vector [AHR (acute hypoxia-response sequence)-GFP] under the control of ADAMTS1 promoter and compared it with the constitutive GFP-expressing vector under the control of CMV (cytomegalovirus promoter-GFP). We transduced AHR-GFP and examined whether GFP signals can be detected under the acute hypoxia. When the human umbilical vein [HUVEC (human umbilical vein endothelial cells)] was transduced under normoxia, there were few GFP signals, while CMV-GFP showed considerable GFP signals. When HUVEC was stimulated with hypoxia, GFP signals from AHR-GFP gene were induced under hypoxic conditions. Notably, the GFP signals peaked at 3 h under hypoxia. In ischaemic hind limb model, transduced AHR-GFP showed hypoxic induction of GFP signals. In summary, we have demonstrated that the AHR system induced the reporter gene expression by acute hypoxia, and its induction is transient. This is the first report showing the unique acute hypoxia-activated gene expression system.

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  • Distribution Pattern of Urine Albumin Creatinine Ratio and the Prevalence of High-Normal Levels in Untreated Asymptomatic Non-Diabetic Hypertensive Patients

    Natsuki Ohmaru, Takaaki Nakatsu, Reishi Izumi, Keiichi Mashima, Misako Toki, Asako Kobayashi, Hiroko Ogawa, Satoshi Hirohata, Satoru Ikeda, Shozo Kusachi

    INTERNAL MEDICINE   50 ( 16 )   1621 - 1629   2011年

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    記述言語:英語   出版者・発行元:JAPAN SOC INTERNAL MEDICINE  

    Background Even high-normal albuminuria is reportedly associated with cardiovascular events.
    Objective We determined the urine albumin creatinine ratio (UACR) in spot urine samples and analyzed the UACR distribution and the prevalence of high-normal levels.
    Patients and Methods The UACR was determined using immunoturbidimetry in 332 untreated asymptomatic non-diabetic Japanese patients with hypertension and in 69 control subjects. The microalbuminuria and macroalbuminuria levels were defined as a UCAR &gt;= 30 and &lt;300 mu g/mg.creatinine and a UCAR &gt;= 300 mu g/mg.creatinine, respectively.
    Results The distribution patterns showed a highly skewed distribution for the lower levels, and a common logarithmic transformation produced a close fit to a Gaussian distribution with median, 25th and 75th percentile values of 22.6, 13.5 and 48.2 mu g/mg.creatinine, respectively. When a high-normal UACR was set at &gt;20 to &lt;30 mu g/mg.creatinine, 19.9% (66/332) of the hypertensive patients exhibited a high-normal UACR. Micro-albuminuria and macroalbuminuria were observed in 36.1% (120/336) and 2.1% (7/332) of the patients, respectively. UACR was significantly correlated with the systolic and diastolic blood pressures and the pulse pressure. A stepwise multivariate analysis revealed that these pressures as well as age were independent factors that increased UACR.
    Conclusion The UACR distribution exhibited a highly skewed pattern, with approximately 60% of untreated, non-diabetic hypertensive patients exhibiting a high-normal or larger UACR. Both hypertension and age are independent risk factors that increase the UACR. The present study indicated that a considerable percentage of patients require anti-hypertensive drugs with antiproteinuric effects at the start of treatment.

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  • Serum Adipocyte Fatty Acid-Binding Protein is Associated With Coronary Lesion Complexity in Patients With Coronary Artery Disease

    Masayuki Doi, Toru Miyoshi, Mutsumi Iwamoto, Kunio Nogami, Kajiya Masashi, Ko Takeda, Satoshi Hirohata, Shozo Kusachi, Hiroshi Ito

    CIRCULATION   122 ( 21 )   2010年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Chronic Kidney Disease is a Strong Predictor Related to the Severity of Coronary Artery Lesion in Patients with Stable Angina Pectoris

    Kazuhiro Dan, Masayuki Ueeda, Hiroaki Ohtsuka, Satoko Ugawa, Nobuhiko Ohnishi, Atsushi Takaishi, Satoshi Hirohata, Shozo Kusachi, Kengo Kusano, Hiroshi Ito

    CIRCULATION   122 ( 2 )   E363 - E364   2010年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • AHR (Acute hypoxia responsive element) As a New Tool Detecting Acute Hypoxia

    Mehmet Zeynel Cilek, Satoshi Hirohata, Omer Faruk Hatipoglu, Yoshifumi Ninomiya

    FASEB JOURNAL   24   2010年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:FEDERATION AMER SOC EXP BIOL  

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  • A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9) expression by chondrocytes during endochondral ossification

    Kanae Kumagishi, Keiichiro Nishida, Tomoichiro Yamaai, Ryusuke Momota, Shigeru Miyaki, Satoshi Hirohata, Ichiro Naito, Hiroshi Asahara, Yoshifumi Ninomiya, Aiji Ohtsuka

    ARCHIVES OF HISTOLOGY AND CYTOLOGY   72 ( 3 )   175 - 185   2009年11月

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    記述言語:英語   出版者・発行元:INT SOC HISTOLOGY & CYTOLOGY  

    A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9) is known to influence aggrecan degradation in endochondral ossification, but its role has not been well understood. In the present study, in vitro gene expression of ADAMTS9 was investigated by RT-PCR in ATDC5 cells in which experimentally chondrogenic differentiation had been induced. We also investigated the protein localization and gene expression pattern of ADAMTS9 in the tibia growth plate cartilage of male mice in a day 1 neonate, 7-week-old young adult, and a 12-week-old adult by immunohistochemistry and in situ hybridization and compared the results with the expression of proliferating cell nuclear antigen (PCNA) and type X collagen for the identification of proliferative and hypertrophic chondrocyte phenotypes, respectively. We found the gene expression of ADAMTS9 by ATDC5 cells as a dual mode, both before the expression of type X collagen and after hypertrophic differentiation. The immunoreactivity of ADAMTS9 was observed in chondrocytes of proliferative and hypertrophic zones in the growth plate. The population of ADAMTS9 positive cells decreased with age. The results of the present study suggest that ADAMTS9 might have a role in aggrecan cleavage around the chondrocytes to allow chondrocyte proliferation and hypertrophy.

    DOI: 10.1679/aohc.72.175

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  • Association of Increased Plasma Adipocyte Fatty Acid-binding Protein With Coronary Artery Disease in Men

    Shunichi Higashiya, Masayuki Doi, Kunio Nogami, Mutsumi Iwamoto, Akihisa Yumoto, Kou Takeda, Masayuki Ueeda, Toru Miyoshi, Satoshi Hirohata, Shozo Kusachi, Yoshifumi Ninomiya, Hiroshi Ito

    CIRCULATION   120 ( 18 )   S397 - S398   2009年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • ADAMTS-1 is an Endothelial Cell-specific Hypoxia-inducible Gene

    Satoshi Hirohata, Faruk O. Hatipoglu, Toru Miyoshi, Hiroko Ogawa, Masanari Obika, Shigeshi Kamikawa, Shozo Kusachi, Hiroshi Itoh, Yoshifumi Ninomiya

    CIRCULATION   120 ( 18 )   S1172 - S1172   2009年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • A Novel Cationic Protein Reduced Infracted Size and Protected Myocytes From Oxidative Stress Through Modification of Akt Signaling

    Shigeshi Kamikawa, Satoshi Hirohata, Syougo Watanabe, Takashi Ohtsuki, Toru Miyoshi, Hiroko Ogawa, Shozo Kusachi, Masaharu Senoo, Yoshifumi Ninomiya, Hiroshi Itoh

    CIRCULATION   120 ( 18 )   S888 - S889   2009年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Regulation of cellular immunity prevents Helicobacter pylori-induced atherosclerosis

    K. Ayada, K. Yokota, K. Hirai, K. Fujimoto, K. Kobayashi, H. Ogawa, K. Hatanaka, S. Hirohata, T. Yoshino, Y. Shoenfeld, E. Matsuura, K. Oguma

    LUPUS   18 ( 13 )   1154 - 1168   2009年11月

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    記述言語:英語   出版者・発行元:SAGE PUBLICATIONS LTD  

    Helicobacter pylori (H. pylori) is a predominant pathogen that causes not only gastroduodenal diseases but also extra-alimentary tract diseases. In this study, we demonstrated that H. pylori infection promoted atherogenesis in heterozygous apoe(+/-) ldlr(+/-) mice. The male mice were fed with high fat diet from the age of 6 weeks. At the age of 16 weeks, development of atherosclerotic lesions was observed in the H. pylori-infected mice, and it seemed to be associated with an elevation of Th1-immune response against H. pylori origin-heat shock protein 60 (Hp-HSP60) and an increment of transendothelial migration of T cells. Subcutaneous immunisation with Hp-HSP60 or H. pylori eradication with antibiotics significantly reduced the progression of atherosclerosis, accompanied by a decline of Th1 differentiation and reduction of their chemotaxis beyond the endothelium. Thus, oral infection with H. pylori accelerates atherosclerosis in mice and the active immunisation with Hp-HSP60 or the eradication of H. pylori with antibiotics can moderate/prevent cellular immunity, resulting in a reduction of atherosclerosis. Lupus (2009) 18, 1154-1168.

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  • Augmentation index is associated with B-type natriuretic peptide in patients with paroxysmal atrial fibrillation 国際誌

    Youko Kaji, Toru Miyoshi, Masayuki Doi, Satoshi Hirohata, Shigeshi Kamikawa, Kosuke Sakane, Tomoki Kitawaki, Shozo Kusachi, Kengo Fukushima Kusano, Hiroshi Ito

    HYPERTENSION RESEARCH   32 ( 7 )   611 - 616   2009年7月

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    記述言語:英語   出版者・発行元:NATURE PUBLISHING GROUP  

    B-type natriuretic peptide (BNP) levels have been shown to be elevated in patients with paroxysmal atrial fibrillation (PAF); however, the underlying mechanisms have not been fully elucidated. Earlier, we reported that an increase in the augmentation index ( AI), which is an index of wave reflection and arterial stiffness, is associated with PAF. In this study, we investigate the relationship between the BNP level and AI in patients with PAF. We enrolled 92 patients with a history of PAF and 90 age- and gender-matched individuals without PAF. AI was calculated using applanation tonometry of the radial artery when all patients were on sinus rhythm. Plasma BNP levels were measured simultaneously. An arterial stiffness parameter, the cardio-ankle vascular index ( CAVI), was also evaluated. The increased AI in patients with PAF correlated with the elevation of the BNP level (r=0.47, P&lt;0.01). When PAF patients were classified into tertiles on the basis of the BNP level, the left atrial volume index, left ventricular mass index, AI and CAVI increased, and mitral annular e&apos; velocity (e&apos;), as an index of left ventricular diastolic pressure, decreased with BNP tertiles. AI was also associated with e&apos; and left ventricular mass index. Multiple regression analysis showed that the AI in PAF patients independently correlated with BNP levels. This study showed that AI was an independent correlate of the BNP level in PAF patients. Left ventricular diastolic dysfunction, which linked to an increase in arterial stiffness, may be involved in the elevated BNP level. Hypertension Research ( 2009) 32, 611-616; doi: 10.1038/hr.2009.62; published online 1 May 2009

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  • ADAMTS1 Is a Unique Hypoxic Early Response Gene Expressed by Endothelial Cells 国際誌

    Omer F. Hatipoglu, Satoshi Hirohata, M. Zeynel Cilek, Hiroko Ogawa, Toru Miyoshi, Masanari Obika, Kadir Demircan, Ryoko Shinohata, Shozo Kusachi, Yoshifumi Ninomiya

    JOURNAL OF BIOLOGICAL CHEMISTRY   284 ( 24 )   16325 - 16333   2009年6月

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    記述言語:英語   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) is a member of the matrix metalloproteinase family. We have previously reported that ADAMTS1 was strongly expressed in myocardial infarction. In this study, we investigated whether hypoxia induced ADAMTS1 and investigated its regulatory mechanism. In hypoxia, the expression level of ADAMTS1 mRNA and protein rapidly increased in endothelial cells, but not in other cell types. Interestingly, the induction of ADAMTS1 by hypoxia was transient, whereas vascular endothelial growth factor induction by hypoxia in human umbilical vein endothelial cells (HUVEC) increased in a time-dependent manner. CoCl(2), a transition metal that mimics hypoxia, induced ADAMTS1 in HUVEC. The phosphatidylinositol 3-kinase inhibitor LY294002 dose-dependently inhibited the increase of ADAMTS1 mRNA expression in hypoxia. We characterized the promoter region of ADAMTS1, and the secreted luciferase assay system demonstrated that hypoxia induced luciferase secretion in the culture medium 4.6-fold in HUVEC. In the promoter region of ADAMTS1, we found at least three putative hypoxia-inducible factor (HIF) binding sites, and the chromatin immunoprecipitation assay revealed HIF-1 binding to HIF binding sites in the promoter region of ADAMTS1 under hypoxia. Recombinant ADAMTS1 protein promoted the migration of HUVEC under hypoxic conditions. In summary, we found that ADAMTS1 is transiently induced by hypoxia in endothelial cells, and its transcription is mediated by HIF-1 binding. Our data indicate that ADAMTS1 is a novel acute hypoxia-inducible gene.

    DOI: 10.1074/jbc.M109.001313

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  • INCREASED mRNA EXPRESSION OF ADAMTS METALLOPROTEINASES IN METASTATIC FOCI OF HEAD AND NECK CANCER 国際誌

    Kadir Demircan, Esra Gunduz, Mehmet Gunduz, Levent Bekir Beder, Satoshi Hirohata, Hitoshi Nagatsuka, Beyhan Cengiz, Mehmet Zeynel Cilek, Noboru Yamanaka, Kenji Shimizu, Yoshifumi Ninomiya

    HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK   31 ( 6 )   793 - 801   2009年6月

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    記述言語:英語   出版者・発行元:JOHN WILEY & SONS INC  

    Background. Although contribution of matrix metalloproteinases in cancer progression and dissemination is now well known, roles of recently discovered metalloproteinases, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), in cancer development and progression remain mostly unknown.
    Methods. Here we examined the mRNA expression pattern of 6 members of ADAMTS aggrecanases (1, 4, 5, 8, 9, and 15) in primary head and neck cancer with and without metastasis by real-time reverse transcriptase-polymerase chain reaction.
    Results. Expression levels of ADAMTS mRNAs were lower in the majority of the primary tumors as compared with the controls, On the other hand, the expression levels of all of the ADAMTS mRNAs except ADAMTS4 were higher in the metastatic foci than in their corresponding primary tumors, which suggest that characteristics of the cancer cell population are different in the primary tumor and metastatic focus.
    Conclusion. Our findings suggest a metastasis model proposing accumulation of a subtype of cancer cells with high metastatic capacity within heterogenous primary tumor cell population. (c) 2009 Wiley Periodicals, Inc. Head Neck 31: 793-801, 2009

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  • The 3’-untranslated Region of ADAMTS1 Regulates Its mRNA Stability.

    Hatipoglu OF, Hirohata S, Yaykasli KO, Cilek MZ, Demircan K, Shinohata R, Yonezawa T, Oohashi T, Kusachi S, Ninomiya Y

    Acta Medica Okayama   63 ( 2 )   79 - 85   2009年4月

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  • ADAMTS9 activation by interleukin 1 beta via NFATc1 in OUMS-27 chondrosarcoma cells and in human chondrocytes. 国際誌

    Kursat Oguz Yaykasli, Toshitaka Oohashi, Satoshi Hirohata, Omer Faruk Hatipoglu, Kiichi Inagawa, Kadir Demircan, Yoshifumi Ninomiya

    Molecular and cellular biochemistry   323 ( 1-2 )   69 - 79   2009年3月

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    記述言語:英語   出版者・発行元:SPRINGER  

    ADAMTS9 is a member of the disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) genes, with aggrecan-degrading activity. It has also been characterized to be reactive and highly activated ADAMTS by IL-1 beta in both chondrosarcoma cells and human chondrocytes (Demircan et al. Arthritis Rheum 52:1451-1460, 2005). In order to understand the regulation of ADAMTS9 gene expression a functional 3.0 kb human ADAMTS9 promoter has been cloned and characterized. A sequence analysis of the promoter revealed the presence of putative binding sites for Nuclear Factor of Activated T cells (NFAT), which is commonly found in the ADAMTS4 and ADAMTS5 promoters. NFATc1 was up-regulated in an activated form by IL-1 beta in human chondrocytes. The IL-1 beta inducible ADAMTS9 expression was inhibited by NFAT inhibitors, FK506 and 11Arg (11R)-VIVIT. Furthermore, direct binding of NFATc1 on distal and proximal promoters of ADAMTS9 was demonstrated by a chromatin immunoprecipitation assay. Promoter-reporter assays supported those results. These findings may provide a better understanding of the regulation of ADAMTS9 expression induced by inflammatory cytokines.

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  • THE 3 &apos;-UNTRANSLATED REGION OF THE ADAMTS1 REGULATES ITS EXPRESSION

    Omer Faruk Hatipoglu, Satoshi Hirohata, Kursat Oguz Yaykasli, Mehmet Zeynel Cilek, Kadir Demircan, Ryoko Shinohata, Shozo Kusachi, Yoshifumi Ninomiya

    IUBMB LIFE   61 ( 3 )   367 - 367   2009年3月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:JOHN WILEY & SONS INC  

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  • IDENTIFICATION OF NF-kappa B BINDING ELEMENTS IN HUMAN ADAMTS9 PROMOTER

    Kadir Demircan, Esra Gunduz, Mehmet Zeynel Cilek, Omer Faruk Hatipoglu, Kursat Oguz Yaykasli, Mehmet Gunduz, Yoshifum Ninomiya, Satoshi Hirohata

    IUBMB LIFE   61 ( 3 )   354 - 354   2009年3月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:JOHN WILEY & SONS INC  

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  • UTILIZATION OF ADAMTSI AS A NEW TOOL FOR DETECTING HYPOXIA

    Mehmet Zeynel Cilek, Satoshi Hirohata, Omer Faruk Hatipoglu, Kadir Demircan, Junko Inagaki, Tomoko Yonezawa, Toshikata Oohashi, Yoshifumi Ninomiya

    IUBMB LIFE   61 ( 3 )   357 - 358   2009年3月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:JOHN WILEY & SONS INC  

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  • Relationship between activin A level and infarct size in patients with acute myocardial infarction undergoing successful primary coronary intervention 国際誌

    Toru Miyoshi, Satoshi Hirohata, Tadahisa Uesugi, Minoru Hirota, Hirornichi Ohnishi, Kunio Nogami, Kunihiko Hatanaka, Hiroko Ogawa, Shinichi Usui, Shozo Kusachi

    CLINICA CHIMICA ACTA   401 ( 1-2 )   3 - 7   2009年3月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE BV  

    Background: Activin A, a member of the transforming growth factor-beta cytokine family, has been suggested to have a role in inflammation. We examined the serum level of activin A in patients with acute myocardial infarction (AMI) undergoing successful primary percutaneous coronary intervention (PCI).
    Methods: The subjects were 30 AMI patients, 20 stable angina pectoris (AP) patients and 20 normal subjects. The serum levels of activin A in AMI patients were measured before PCI and on days 1, 2, 7, and 14.
    Results: Activin A levels before PCI in AMI patients (557 +/- 255 pg/ml) showed a significantly higher value than those in AP patients (364 +/- 159 pg/ml) and control subjects (316 +/- 144 pg/ml). Increased serum activin A level before PCI was decreased on day 2, and then gradually re-elevated on days 7 and 14, The serum activin A level before PCI was correlated with log-transformed peak creatine kinase (CK) as a surrogate of infarct size (r=0.48, p=0.008). Stepwise multiple regression analysis demonstrated that the serum activin A level before PCI was an independent predictor of peak CK.
    Conclusions: The serum activin A level, increased in AMI, was positively correlated with peak CK and CK-MB levels which are measures of infarction size. (C) 2008 Elsevier B.V. All rights reserved.

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  • Human eosinophil cationic protein enhances stress fiber formation in Balb/c 3T3 fibroblasts and differentiation of rat neonatal cardiomyocytes 国際誌

    Takayuki Fukuda, Miki Iwata, Midori Kitazoe, Takashi Maeda, David Salomon, Satoshi Hirohata, Katsuyuki Tanizawa, Shun&apos;ichi Kuroda, Masaharu Seno

    GROWTH FACTORS   27 ( 4 )   228 - 236   2009年

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    記述言語:英語   出版者・発行元:TAYLOR & FRANCIS LTD  

    We found that eosinophil cationic protein (ECP) stimulated the growth of mouse Balb/c 3T3 fibroblasts. ECP-treated 3T3 cells were more flattened and exhibited enhanced stress fiber formation. The enhancement of cytoskeleton after addition of recombinant ECP appeared stable and was able to inhibit disassembly of actin filaments that was induced by fibroblast growth factor-2. The ROCK inhibitor, Y-27632, abrogated this enhancement on stress fiber formation that was induced by ECP indicating the involvement of Rho/ROCK signaling pathway. The effect of ECP was assessed on the differentiation of primary cardiomyocytes derived from rat neonatal heart since the development of actin filaments is significantly related with organization of stress fibers. As the result, both beating rate and the expression of cardiac muscle specific markers such as atrial natriuretic factor were enhanced in the presence of ECP. Thus ECP may also function as a cardiomyocyte differentiation factor.

    DOI: 10.1080/08977190902987149

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  • Increased Augmentation Index of the Radial Pressure Waveform in Patients with Paroxysmal Atrial Fibrillation 国際誌

    Masayuki Doi, Toru Miyoshi, Satoshi Hirohata, Akihiro Iwabu, Youkou Tominaga, Youko Kaji, Shigeshi Kamikawa, Kosuke Sakane, Tomoki Kitawaki, Kengo F. Kusano, Shozo Kusachi

    CARDIOLOGY   113 ( 2 )   138 - 145   2009年

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    記述言語:英語   出版者・発行元:KARGER  

    Objective: The augmentation index, a marker of wave reflection, has been reported to reflect vascular properties and to determine left ventricular (LV) characteristics. We investigated the relationship between the augmentation index and paroxysmal atrial fibrillation (AF). Methods: A total of 244 outpatients (122 patients with paroxysmal AF and 122 age-, and gender-matched controls without paroxysmal AF) were examined during sinus rhythm. The augmentation index was calculated from the radial arterial waveform using applanation tonometry methods. Results: After adjusting for age, gender, heart rate, and medications, the augmentation index was significantly higher in patients with paroxysmal AF than in subjects without paroxysmal AF (means +/- SE: 88.9 +/- 1.0 and 81.8 +/- 1.0%, respectively; p &lt; 0.001). In all subjects, an increase in the augmentation index was significantly correlated with LV hypertrophy and left atrial enlarge ment. Multiple logistic analysis revealed that an increase in the augmentation index was significantly related with paroxysmal AF, and the adjusted odds ratio of paroxysmal AF was approximately 1.8 for each 10% augmentation index increase (p &lt; 0.01). Conclusion: An increase in the augmentation index was independently associated with paroxysmal AF. This result suggests that enhanced wave reflection may be related to the development of AF. Copyright (C) 2008 S. Karger AG, Basel

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  • Serum N-3 Polyunsaturated Fatty Acid Levels Correlate With the Extent of Coronary Plaques and Calcifications in Patients With Acute Myocardial Infarction

    Masayuki Ueeda, Takenori Doumei, Yoichi Takaya, Ryoko Shinohata, Yusuke Katayama, Nobuhiko Ohnishi, Atsushi Takaishi, Toru Miyoshi, Satoshi Hirohata, Shozo Kusachi

    CIRCULATION JOURNAL   72 ( 11 )   1836 - 1843   2008年11月

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    記述言語:英語   出版者・発行元:JAPANESE CIRCULATION SOC  

    Background The relationship between serum fatty acid levels and the extent of coronary plaques and calcification was examined in patients with acute myocardial infarction (AMI).
    Methods and Results The serum levels of the n-3 polyunsaturated fatty acids (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) and the n-6 polyunsaturated fatty acids (arachidonic acid (AA) and dihomo-(gamma-linolenic acid (DGLA)) were determined using gas chromatography on admission of 95 consecutive patients with their first AMI and 17 controls. Using multidetector-row computed tomography, soft plaques and calcification lesions were scored according to the extent of coronary involvement. Serum logarithmic transformed (log) EPA and logDHA levels were inversely correlated with soft plaque scores (r=-0.546, p &lt; 0.0001 and r= -0.377, p &lt; 0.0001, respectively). Serum logAA and logDGLA levels were not significantly correlated with soft plaque scores. Serum logEPA and logDHA levels were significantly, but weakly, correlated with calcification scores. Multivariate analysis with clinical characteristics and risk factors selected serum n-3 polyunsaturated fatty acid levels as independent factors associated with the extent of coronary soft plaques.
    Conclusion The present study demonstrates a significant correlation between serum n-3 polyunsaturated fatty acid levels and the extent of coronary soft plaques and calcification in AMI patients. (Circ J 2008; 72: 1836-1843)

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  • The Impact of Increased Augmentation Index of Radial Pressure Waveform on Paroxysmal Atrial Fibrillation

    Youko Kaji, Toru Miyoshi, Masayuki Doi, Satoshi Hirohata, Tadahisa Uesugi, Shigeshi Kamikawa, Kosuke Sakane, Shozo Kusachi, Kengo F. Kusano

    CIRCULATION   118 ( 18 )   S730 - S730   2008年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Serum Adipocyte Fatty Acid-Binding Protein Levels are Independently Associated with Coronary Atherosclerosis

    Toru Miyoshi, Atsushi Hirohata, Shinichi Usui, Keizo Yamamoto, Kazuyoshi Hina, Satoshi Hirohata, Shozo Kusachi, Yoshifumi Ninomiya, Kengo F. Kusano

    CIRCULATION   118 ( 18 )   S470 - S470   2008年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Association of corrected QT dispersion with symptoms improvement in patients receiving cardiac resynchronization therapy

    Kazuyoshi Hina, Hiroshi Kawamura, Takashi Murakami, Keizo Yamamoto, Hirosuke Yamaji, Masaaki Murakami, Satoshi Hirohata, Hiroko Ogawa, Kohsuke Sakane, Shozo Kusachi

    HEART AND VESSELS   23 ( 5 )   325 - 333   2008年9月

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    記述言語:英語   出版者・発行元:SPRINGER  

    Cardiac resynchronization therapy (CRT) is theoretically expected to affect repolarization as well as depolarization. We studied the effects of CRT on corrected QT (QTc) dispersion in association with symptomatic improvement. QTc dispersion was analyzed in 26 consecutive patients (67 +/- 6 years old, 18 men and 8 women) who underwent CRT. CRT responders and nonresponders were defined as patients showing and not showing &gt;= 1 class New York Heart Association symptomatic improvement 3 months after CRT, respectively. QTc interval, QRS width, and QTc dispersion were measured automatically from digital data using an analyzing system. There were 18 CRT responders and 8 nonresponders among the patients. CRT responders showed significantly larger QTc dispersion than CRT nonresponders before CRT (102 +/- 26 vs 40 +/- 12 ms, P &lt; 0.01). A significant decrease in QTc dispersion by CRT was observed in responders (102 +/- 26 to 52 +/- 15 ms, P &lt; 0.01). In contrast, QTc dispersion was not decreased by CRT in nonresponders (40 +/- 12 to 39 +/- 11 ms, not significant). The difference observed before CRT was thus abolished after CRT (52 +/- 15 vs 39 +/- 11 ms, not significant). Baseline values and changes in QRS width or QTc, as well as asynchrony of wall motion determined by tissue Doppler imaging, were not different between CRT responders and nonresponders before CRT. The present study with a small number of patients shows the potential utility of QTc dispersion for distinguishing CRT responders from CRT nonresponders before CRT, and warrants further study with a greater number of patients.

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  • Prone position is essential for detection of pulmonary vein pseudostenosis by enhanced multidetector computed tomography in patients who undergo pulmonary vein isolation

    Hirosuke Yamaji, Kazuyoshi Hina, Hiroshi Kawamura, Takashi Murakami, Masaaki Murakami, Keizo Yamamoto, Atsushi Hirohata, Toru Miyoshi, Satoshi Hirohata, Shozo Kusachi

    CIRCULATION JOURNAL   72 ( 9 )   1460 - 1464   2008年9月

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    記述言語:英語   出版者・発行元:JAPANESE CIRCULATION SOC  

    Background pulmonary vein (PV) stenosis is a major complication of PV isolation (PVI) by catheter ablation, so in the present study the optimal position for detecting PV stenosis on enhanced multidetector computed tomography (MDCT) image acquisition was determined.
    Methods and Results The 64-slice enhanced MDCT was carried out before and after PVI in 116 consecutive patients with atrial fibrillation while they were in the prone position, as well as while supine. The supine position MDCT image showed &gt; 50% diameter stenosis of the PV in 11 (9%) patients before PVI (% diameter stenosis: mean 55 +/- 4%, range 51-65%). Greater than &gt; 50% diameter stenosis was seen in the left inferior PV in all 11 patients. The prone position attenuated the PV stenosis findings in the MDCT images in all 11 patients (mean 9 +/- 6%, range 2-18%). Stenosis visualized on images acquired in the supine position was, therefore, concluded to be pseudostenosis caused by descending aorta compression. At 3 months after PVI, no significant changes in PV diameter were observed in these 11 patients.
    Conclusion The present study demonstrated that the prone position is essential for eliminating PV pseudostenosis observed oil supine-position enhanced MDCT images. The results also indicate that preexisting PV organic stenosis is rare.

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  • Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen anti body-induced arthritis mouse model

    Y. Nasu, K. Nishida, S. Miyazawa, T. Komiyama, Y. Kadota, N. Abe, A. Yoshida, S. Hirohata, A. Ohtsuka, T. Ozaki

    OSTEOARTHRITIS AND CARTILAGE   16 ( 6 )   723 - 732   2008年6月

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    記述言語:英語   出版者・発行元:ELSEVIER SCI LTD  

    Objective: To investigate the effect of the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), on joint inflammation and cartilage degeneration in a collagen antibody-induced arthritis (CAIA) mouse model.
    Methods: CAIA mice were given daily subcutaneous injections of various concentrations of TSA (0, 0.5, 1.0, and 2.0 mg/kg) and various parameters were monitored for 14 days. On Day 15, the hind paws were examined histologically. To investigate the effects of TSA on the expressions of matrix metal lop roteinase (MMP)-3, MMP-13, tissue inhibitor of MMP-1 (TIMP-1), and acetyl-H4 by chondrocytes, another group of mice was sacrificed on Day 6. In vitro direct effect of TSA was examined by real-time PCR for mRNA of type II collagen, aggrecan, MMP-3, and MMP-13 in murine chondrogenic ATDC5 cells after pro-inflammatory cytokine stimulation.
    Results: In the TSA-treated group, clinical arthritis was significantly ameliorated in a dose-dependent manner. The severity of synovial inflammation and the cartilage destruction score were significantly lower in the TSA 2.0 mg/kg group compared to the other TSA-treated groups. On immunohistochemistry, the number of MMP-3 and MMP-13-positive chondrocytes was significantly lower in the TSA 2.0 mg/kg group than in the control group. In contrast, the number of TIMP-II-positive cells and acetyl-histone H4-positive cells was significantly higher in the TSA 2.0 mg/kg group than in the control group. TSA suppressed interleukin 1-beta and tumor necrosis factor-a-stimulated up-regulation of MMP-3, but not MMP-13 mRNA expression by ATDC5.
    Conclusion: The systemic administration of TSA ameliorated synovial inflammation in CAIA mice. Subsequently cartilage destruction was also suppressed by TSA, at least in part, by modulating chondrocyte gene expression. (C) 2007 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

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  • siRNA silencing reveals role of vascular cell adhesion molecule-1 in vascular smooth muscle cell migration 国際誌

    Erik J. Petersen, Toru Miyoshi, Zuobiao Yuan, Satoshi Hirohata, Jin Zhong Li, Weibin Shi, John F. Angle

    ATHEROSCLEROSIS   198 ( 2 )   301 - 306   2008年6月

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    Vascular cell adhesion molecule-1 (VCAM-1) is an adhesion molecule expressed by endothelial cells for recruitment of leukocytes during inflammation. It is also abundantly expressed by smooth muscle cells in atherosclerotic lesions and in injured arteries. In this study, we examined the role of VCAM-1 in smooth muscle cell migration. Smooth muscle cells were isolated from the aorta of C57BL/6 mice and transfected with short interfering RNAs (siRNAs) targeting VCAM-1. Inhibition on VCAM-1 expression by siRNAs was assessed by Western blot analysis, RT-PCR and by measuring soluble VCAM-1 concentrations in the incubation medium. One siRNA that showed greater suppression on VCAM-1 expression was used for migration assay. A single scratch wound was made on 70% confluent cells and cells migrated from wounded monolayer were counted 24 and 48 h after injury. Treatment with VCAM-1 siRNA resulted in a significant reduction in the number of migrated cells. This siRNA also exhibited a minor effect on smooth muscle cell proliferation. Thus, our findings indicate that VCAM-1 is necessary for the migration of smooth muscle cells and interfering VCAM-1 expression could be an effective approach to prevention and treatment of atherosclerosis and restenosis. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

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  • Higher incidence and serum levels of minor cardiac biomarker elevation in sirolimus-eluting stent (Cypher) than bare metal stent implantations

    Tetsushi Seitou, Masaaki Murakami, Issei Komatsubara, Hiroshi Kawamura, Keizo Yamamoto, Kazuyoshi Hina, Satoshi Hirohata, Ryoko Shinohata, Yoshifumi Ninomiya, Shozo Kusachi

    CORONARY ARTERY DISEASE   19 ( 2 )   63 - 69   2008年3月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Objectives Minor cardiac biomarker elevation after percutaneous coronary intervention has long-term prognostic significance. The sirolimus-eluting stent (Cypher) has been reported to require high postinflation pressure for optimal implantation. We examined the incidence of minor cardiac biomarker elevation induced by Cypher implantation.
    Methods We measured the serum concentration of cardiac troponin-I (cTnl) 24 h after stenting and those of creatine kinase isoenzyme MB and creatine kinase before, immediately after, and 6, 12 and 24 h after implantation in patients who underwent Cypher stent (CS group; n = 53) or bare metal stent (BMS group; n = 57) implantation.
    Results No significant difference in clinical background was observed between the two groups. When a cutoff cTnl value of 0.50ng/ml was used, the CS group showed a significantly higher incidence of cTnl elevation (35.8%, 19/53) than the BMS group (14.0%, 8/57) (P&lt;0.05). Similarly, the incidence of cTnl &gt;= 0.03 ng/ml tended to be higher in the CS group (88.7%, 47/53) than in the BMS group (73.7%, 42/57: 0.05&lt;P&lt;0.10). Furthermore, the CS group showed significantly higher cTnl levels than the BMS group (1.32 +/- 2.38 vs. 0.34 +/- 0.91 ng/ml. P&lt; 0.001). Essentially, similar results were obtained for serum creatine kinase isoenzyme MB and creatine kinase. Among clinical, lesion and procedural characteristics, postinflation pressure for stenting was significantly higher only in the CS group (18.2 +/- 2.8 atm) than in the BMS group (14.0 +/- 2.7 atm) (P&lt; 0.001).
    Conclusions The results demonstrated that CS implantation increases the incidence of minor cardiac biomarker elevation compared with BMS. The difference in postinflation pressure could account for the results.

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  • Increased augmentation index of radial pulse wave in patients with paroxysmal atrial fibrillation

    Toru Miyoshi, Masayuki Doi, Youko Kaji, Satoshi Hirohata, Shigeshi Kamikawa, Shozo Kusachi, Tohru Ohe

    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY   51 ( 10 )   A304 - A304   2008年3月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER SCIENCE INC  

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  • Association of augmentation index of radial pressure wave form with diurnal variation pattern of blood pressure in untreated patients with essential hypertension 国際誌

    Ryoko Shinohata, Takaaki Nakatsu, Yoko Yuki, Aya Nishitani, Keiichi Mashima, Shinji Toyonaga, Hiroko Ogawa, Satoshi Hirohata, Shinichi Usui, Tomoki Kitawaki, Shozo Kusachi

    JOURNAL OF HYPERTENSION   26 ( 3 )   535 - 543   2008年3月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Objectives The augmentation index of the radial pulse wave has been reported to be a sensitive aortic stiffness marker in relatively young but not in older individuals. We studied the relationship between augmentation index and the diurnal blood pressure profiles.
    Patients and methods Twenty-four-hour ambulatory blood pressure monitoring was performed in 90 untreated patients with uncomplicated essential hypertension. The patients were classified into four groups: dippers, extreme dippers, nondippers, and risers. Augmentation index was calculated as the percentage of the second systolic peak relative to the first systolic peak.
    Results No significant differences in the averaged whole 24-h systolic or diastolic blood pressure were observed in the whole set of patients or in subgroup patients with age 60 years or under. In the whole set of patients (58.7 +/- 12.9 years), there were significant differences in augmentation index between patients with abnormal (other than dippers) and normal diurnal blood pressure profiles (dippers). In subgroup patients with age 60 years or below (49.1 +/- 9.1 years, n = 48), the abnormal diurnal blood pressure profile group showed significantly higher augmentation index (89.6 +/- 10.3%) than dippers (80.5 +/- 11.8%). The area under the curve in the receiver operating characteristics curve for distinguishing between dippers than other dippers was 0.73 (P &lt; 0.01). Multivariate analysis demonstrated that abnormal diurnal blood pressure profile was independently associated with increase in augmentation index. In contrast, these relationships were not significant in the over 60 years subgroup patients (69.8 +/- 5.6 years old, n = 42).
    Conclusions The present study revealed that augmentation index was associated with dipping blood pressure patterns in untreated hypertensive patients aged 60 years or younger. Augmentation index determination would be useful for initial assessment in connection with possible abnormal diurnal blood pressure variability in patients with age 60 years or younger.

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  • Serum interferon-gamma-inducible protein 10 level was increased in myocardial infarction patients, and negatively correlated with infarct size 国際誌

    Kazuya Koten, Satoshi Hirohata, Toru Miyoshi, Hiroko Ogawa, Shinichi Usui, Ryoko Shinohata, Mutsumi Iwamoto, Tomoki Kitawaki, Shozo Kusachi, Kosaku Sakaguchi, Tohru Ohe

    CLINICAL BIOCHEMISTRY   41 ( 1-2 )   30 - 37   2008年1月

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    記述言語:英語   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Objectives: We examined the serum levels of interferon-gamma-inducible protein 10 (IP-10), an inflammation-induced chemokine, in acute myocardial infarction (AMI).
    Design and methods: The subjects were 33 AMI patients, 20 stable angina pectoris patients (AP) and 20 normal subjects. In AMI patients, blood samples were collected before percutaneous coronary intervention (PCI) and on days 3, 7 and 28.
    Results: Patients with AMI showed significantly higher serum IP-10 levels (137.5 +/- 79.8 pg/mL) than control subjects (91.2 +/- 40.1 pg/mL) and patients with AP (93.3 +/- 41.1 pg/mL). The serum IP-10 level before PCI was negatively correlated with infarct size, as indicated by cumulative release of creatine kinase (CK) and peak CK and its isoenzyme CK-MB Stepwise multiple regression analysis revealed that the serum IP-10 level before PCI was an independent predictor of cumulative CK release.
    Conclusions: The serum IP-10 level was increased in AMI, and a higher level of serum IP- 10 before PCI may be informative regarding infarct size. (c) 2007 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

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  • Increased blood pressure levels relative to subjective feelings of intensity of exercise determined with the borg scale in male patients with hypertension 国際誌

    Eriko Mayumi, Aya Nishitani, Yoko Yuki, Takaaki Nakatsu, Shinji Toyonaga, Keiichi Mashima, Hiroko Ogawa, Satoshi Hirohata, Shinichi Usui, Ryoko Shinohata, Kousaku Sakaguchi, Shozo Kusachi

    CLINICAL AND EXPERIMENTAL HYPERTENSION   30 ( 3-4 )   191 - 201   2008年

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    記述言語:英語   出版者・発行元:TAYLOR & FRANCIS INC  

    We examined the hemodynamic responses to exercise and symptoms in 37 male patients with untreated essential hypertension, and compared the findings with those in 32 age-matched healthy male volunteers by performing a graded symptom-limited exercise test using a bicycle ergometer. The subjective feeling of intensity of exercise was determined using the Borg scale. In the relationship between Borg scores and blood pressure (BP), patients with hypertension showed higher systolic BP and diastolic BP relative to the Borg scores than the controls. Consequently, patients with hypertension showed significantly higher systolic BP with Borg scores &lt;= 3 (subjective symptoms &lt;= moderately hard) than the controls (177.8 +/- 27.0 vs. 143.7 +/- 17.9 mmHg, p 0.0001). Similarly, significantly higher diastolic BP with Borg scores 3 was observed in patients with hypertension than in the controls (101.6 +/- 12.0 vs. 82.6 +/- 11.6 mmHg, p &lt; 0.0001). The pulse pressure with Borg scores 3 was also significantly higher in patients with hypertension than in the controls (76.2 +/- 20.6 vs. 61.0 +/- 13.6 mmHg, p &lt; 0.0001). Hypertensive patients showed a decrease in the high-frequency power of heart rate variability at initial low-load exercise. In conclusion, the present study revealed that there was a greater BP response relative to the Borg score in patients with hypertension than in the controls. Autonomic nerve activity may contribute to some extent to these different relations. A determination of the relationship between the subjective feeling of intensity of the exercise and BP levels caused by a given intensity of load is essential before exercise training in patients, at least in males, with hypertension to avoid increasing the risk of cardiovascular events in association with excessive exercise training.

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  • Association of new arterial stiffness parameter, the cardio-ankle vascular index, with left ventricular diastolic function

    Kosuke Sakane, Toru Miyoshi, Masayuki Doi, Satoshi Hirohata, Youko Kaji, Shigeshi Kamikawa, Hiroko Ogawa, Kunihiko Hatanaka, Tomoki Kitawaki, Shozo Kusachi, Kazuhide Yamamoto

    Journal of Atherosclerosis and Thrombosis   15 ( 5 )   261 - 268   2008年

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    記述言語:英語   出版者・発行元:Japan Atherosclerosis Society  

    Aim: Pulse wave velocity has been used as an index of aortic stiffness. Recently, the cardio-ankle vascular index (CAVI), which reflects the stiffness of the aorta independently of blood pressure, has been developed. In this study, we analyzed the relationship between CAVI and left ventricular (LV) diastolic dysfunction. Methods: A total of 119 patients were referred for echocardiography to evaluate ventricular function. Patients with reduced systolic function were excluded. Patients were divided on the basis of normal or reduced LV diastolic function determined by echocardiography. CAVI was measured using an automatic waveform analyzer. Results: CAVI was significantly higher in patients with reduced LV diastolic function than those with normal LV diastolic function (9.0 ± 1.1 and 8.5 ± 1. 1, p= 0.009). Multiple linear regression analysis revealed that CAVI was independently associated with the ratio of peak early diastolic velocity to peak atrial diastolic velocity an left atrial diameter. When patients were classified on the basis of CAVI quartiles, multiple logistic regression analysis demonstrated that the highest quartile of CAVI showed an increased odds ratio for the presence of IV diastolic dysfunction. Conclusion: The present study revealed that an increased CAVI was independently associated with LV diastolic dysfunction in patient's with preserved systolic function.

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  • OA軟骨破壊におけるアグリカナーゼの役割

    鉄永智紀, 広畑 聡, 西田圭一郎

    関節外科   27   221 - 227   2008年

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  • Serum activin a level is associated with infarct size in patients with acute myocardial infarction who undergo successful primary percutaneous coronary intervention

    Toru Miyoshi, Satoshi Hirohata, Tadahisa Uesugi, Minoru Hirota, Hiromichi Ohnishi, Kunio Nogami, Shozo Kusachi, Tohru Ohe

    CIRCULATION   116 ( 16 )   711 - 711   2007年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Antibodies against heat shock protein 60 derived from Helicobacter pylori: Diagnostic implications in cardiovascular disease

    Tomoyuki Okada, Kiyoshi Ayada, Shinichi Usui, Kenji Yokata, Jinhua Cui, Yoshiro Kawahara, Tomoki Inaba, Satoshi Hirohata, Motowo Mizuno, Daisuke Yamamoto, Shozo Kusachi, Eiji Matsuura, Keiji Oguma

    JOURNAL OF AUTOIMMUNITY   29 ( 2-3 )   106 - 115   2007年9月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD  

    Immune responses against heat shock protein 60 (HSP60) of pathogen-origin are thought to be defensive events which, due to molecular mimicry, misdirect to a human counterpart. Therefore, atherosclerosis may be serologically predicted by anti-HSP60 antibodies (Abs). In the present study, we analyzed the clinical prevalence of the serum IgG Abs against Helicobacter pylori (Hp)-derived HSP60 (Hp-HSP60) or its peptide fragments in patients with cardiovascular disease (CVD; n = 250), as compared to those in age- and gender-matched non-CVD patients (n = 293). Anti-Hp cell lysate Abs frequently appeared in Hp-infected patients who were not associated with CVD. In contrast, Abs against the particular amino acid sequence Hp-HSP60(II3) (II3 region, Glu(141)-Leu(160), in Hp-HSP60) predominantly appeared in CVD patients, as well as IgG anti-human HSP60 (Hu-HSP60(w)). Furthermore, neither titer of anti-Hp-HSP60(113) nor anti-Hu-HSP60(w) Abs was correlated with the levels of high sensitivity C-reactive protein (hsCRP). This data strongly suggested that IgG anti-Hp-HSP60(II3) Abs cross-reacted with Hu-HSP60(w) were independent diagnostic markers relevant to CVD. Further, the 20 amino acid residues (Glu(141)-Leu(160)) might be predominant CVD-associated epitopes that induce anti-Hu-HSP60 auto-Abs, whose location was predicted in the tertiary structure of Hu-HSP60. (c) 2007 Elsevier Ltd. All rights reserved.

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  • Use of plasma B-Type natriuretic peptide level to identify asymptomatic hypertensive patients with abnormal diurnal blood pressure variation profiles: nondippers, extreme dippers, and risers 国際誌

    Takaaki Nakatsu, Ryoko Shinohata, Keiichi Mashima, Yoko Yuki, Aya Nishitani, Shinji Toyonaga, Hiroko Ogawa, Satoshi Hirohata, Shinichi Usui, Shozo Kusachi

    HYPERTENSION RESEARCH   30 ( 7 )   651 - 658   2007年7月

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    記述言語:英語   出版者・発行元:JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE  

    We examined the relationship between plasma B-type natriuretic peptide (BNP) level and diurnal variability pattern of blood pressure (BP). Twenty-four-hour ambulatory BP monitoring was performed in 98 patients with asymptomatic essential hypertension, and the patients were classified into four groups according to their circadian BP variation profiles: dippers (n=29), nondippers (n=36), extreme dippers (n=19), and risers (n=14). Plasma BNP was measured by enzyme immunoassay. Based on the distribution pattern of BNP values, the values were analyzed after logarithmic transformation. Significant differences in plasma BNP levels among the types of circadian BP variations were demonstrated by analysis of variance (p &lt; 0.0005). Nondippers and risers showed significantly higher plasma BNP levels (mean [range: -1 SD and +1 SD]: 16.1 [6.3, 41.6) pg/mL and 29.2 [15.9, 53.4] pg/mL, respectively) than dippers (8.4 [3.7, 19.1] pg/mL). The area under the receiver operating characteristics curve for distinguishing patients with abnormal circadian BP variation from those with normal variation was 0.72, indicating that plasma BNP levels were useful for distinguishing between these patients. Specificity of 69% and sensitivity of 72% were obtained with a cut-off value of 10.5 pg/mL (log plasma BNP, 1.02) for distinguishing the abnormal diurnal BP profile group from the normal group. In conclusion, hypertensive patients with abnormal diurnal BP variation patterns (nondippers, extreme dippers, and risers) showed higher plasma BNP levels than those with normal circadian BP variation (dippers). Plasma BNP level is clinically useful for the identification of hypertensive patients who have abnormal circadian BP variability, which increases the risk of cardiovascular events.

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  • Safety of and tolerance to adenosine infusion for myocardial perfusion single-photon emission computed tomography in a Japanese population

    Kunihiko Hatanaka, Masayuki Doi, Satoshi Hirohata, Shigeshi Kamikawa, Yoko Kaji, Tsutomu Katoh, Shozo Kusachi, Yoshifumi Ninomiya, Tohru Ohe

    CIRCULATION JOURNAL   71 ( 6 )   904 - 910   2007年6月

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    記述言語:英語   出版者・発行元:JAPANESE CIRCULATION SOCIETY  

    Background Adenosine has been available for use in myocardial perfusion single-photon emission computed tomography (SPECT) in Japan since 2005. The purpose of this study was to evaluate the safety of and tolerance to thallium-201 myocardial perfusion SPECT with intravenous adenosine infusion in Japanese patients with suspected coronary artery disease.
    Methods and Results Two hundred and six consecutive patients who underwent an adenosine infusion (120 mu g center dot kg(-1) center dot min(-1)) SPECT at Sumitomo Besshi Hospital (Niihama, Japan) were investigated. The effects of adenosine infusion were monitored for each patient. A coronary angiography was performed in 81 patients. Adenosine infusion significantly decreased blood pressure and increased heart rate. Adverse reactions were observed in 161 patients (78.2%). Most reactions were transient, disappearing soon after the termination of adenosine infusion. No serious adverse reactions, such as acute myocardial infarction or death, occurred. Adenosine infusion was terminated in 3 patients (1.5%) because of near syncope or sustained 2:1 atrioventricular block. Electrocardiographic changes occurred in 15 patients (7.3%). Self-assessed scoring after SPECT showed that the patients were very tolerant (74.6% of 177 patients) of adenosine infusion myocardial SPECT. The sensitivity and specificity were 75.0% and 69.7%, respectively.
    Conclusions Adenosine infusion myocardial SPECT is safe and well tolerated in the Japanese population, despite the frequent occurrence of minor adverse reactions.

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  • Development of an automatic Doppler flow signal detection system: variability of pulmonary and aortic peak flow velocity

    Chiho Morita, Takaaki Nakatsu, Shozo Kusachi, Tomoki Kitawaki, Shinichi Usui, Kazuo Tobe, Shinji Toyonaga, Hiroko Ogawa, Satoshi Hirohata, Yasushi Shiratori

    JOURNAL OF MEDICAL ULTRASONICS   34 ( 1 )   37 - 42   2007年

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    記述言語:英語   出版者・発行元:SPRINGER TOKYO  

    Purpose. Automatic Doppler flow signal detection systems can provide beat-to-beat information for large blood vessels. We have developed new equipment for automatic measurement of Doppler flow signals. The reliability of the system was examined, and the variability of aortic and pulmonary peak flow velocity was determined.
    Methods. We measured peak flow velocity using a newly developed system in healthy volunteers and patients with atrial fibrillation. Analysis of variability of peak flow velocity was performed with maximal entropy methods.
    Results. In Bland-Altman plots, the mean and standard deviation (SD) of differences in aortic peak flow velocities between the automatic and manual measurements were 0.22 +/- 0.75cm/s and 0.85 +/- 0.38cm/s, respectively, in five normal volunteers. Moreover, less than 5% of the plotted points were beyond 2 SD of the differences. Furthermore, good reproducibility was demonstrated using Bland-Altman plots and Pearson&apos;s correlation analysis. Identical reliability was obtained in patients with atrial fibrillation. The same results were obtained for pulmonary peak flow velocity. In five healthy subjects, aortic and pulmonary peak flow showed standard deviations of 7.2 +/- 2.4 and 3.8 +/- 0.6cm/s, respectively, and coefficients of variation of 6.1% +/- 1.0% and +/- 1.1%, respectively, in time-domain variability. Similarly, frequency-domain variability was obtained for both peak flow velocities.
    Conclusion. The present study demonstrated the reliability of a newly developed automatic Doppler flow signal detection system. Using this system, the present study demonstrated for the first time aortic and pulmonary peak flow velocity variability. The present analytical methods may have considerable potential for studying aortic and/or pulmonary flow variability in connection with cardiac performance and prognosis of cardiac disease.

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  • The balance of n6/n3 polyunsaturated fatty acid (PUFAs) is an important determinant factor of prognosis after acute myocardial infarction

    Takenori Domei, Masayuki Ueeda, Yoichi Takaya, Nobuhiko Ohnishi, Atsushi Takaishi, Masanobu Imai, Satoshi Hirohata, Shozo Kusachi, Toru Ohe

    CIRCULATION   114 ( 18 )   463 - 463   2006年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Statin treatment accelerated neovessel formation in the border zone of the infarcted heart: Architectural study of vascular casts by scanning electron microscopy

    Mutsumi Iwamoto, Satoshi Hirohata, Masahiko Maruyama, Kunihiko Hatanaka, Hiroko Ogawa, Yasushi Shiratori, Shozo Kusachi, Tohru Ohe

    CIRCULATION   114 ( 18 )   206 - 206   2006年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Decreased serum levels of interferon gamma inducible protein 10 (IP-10) in acute myocardial infarction patients after successful primary percutaneous coronary intervention are associated with a smaller infarct size

    Satoshi Hirohata, Kazuya Koten, Shinichi Usui, Hiroko Ogawa, Hitoshi Yamawaki, Masanari Obika, Mutsurni Iwamoto, Yasushi Shiratori, Shozo Kusachi, Tohru Ohe

    CIRCULATION   114 ( 18 )   744 - 744   2006年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Tumor-specific expression of the RGD-alpha 3(IV)NC1 domain suppresses endothelial tube formation and tumor growth in mice 国際誌

    Toru Miyoshi, Satoshi Hirohata, Hiroko Ogawa, Masayuki Doi, Masanari Obika, Tomoko Yonezawa, Yoshikazu Sado, Shozo Kusachi, Satoru Kyo, Seiji Kondo, Yasushi Shiratori, Billy G. Hudson, Yoshifumi Ninomiya

    FASEB JOURNAL   20 ( 11 )   1904 - +   2006年9月

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    記述言語:英語   出版者・発行元:FEDERATION AMER SOC EXP BIOL  

    Angiogenesis plays an essential role in tumor growth. This study investigated expression of the noncollagenous domain of alpha 3(IV) collagen (alpha 3(IV) NC1) transduced into tumors and its inhibition of tumor growth. We hypothesized that if a human telomerase reverse transcriptase (hTERT) promoter-driven RGD motif containing alpha 3(IV) NC1 (hTERT/ RGD-alpha 3(IV) NC1) were expressed in telomerase-expressing tumor cells, it would inhibit tumor growth by its anti-angiogenic property. Adenoviral transduction of hTERT/ RGD-alpha 3(IV) NC1 expressed RGD-alpha 3(IV) NC1 in hTERT-positive tumor cell lines. However, hTERT/ RGD-alpha 3(IV) NC1 did not express RGD-alpha 3(IV) NC1 in hTERT-negative cells such as keratinocytes and fibroblasts. The secreted RGD-alpha 3(IV) NC1 in the conditioned medium from tumor cells inhibited cell proliferation as well as tube formation in cultured endothelial cells, but had no effect on other types of cells. In an in vivo model, adenoviral hTERT/ RGD-alpha 3(IV) NC1 gene therapy showed limited expression of RGD-alpha 3(IV) NC1 in tumors and resulted in a significant decrease of vessel density in tumors. The growth of subcutaneous (s. c.) tumors in nude mice was significantly suppressed by treatment with hTERT/ RGD-alpha 3(IV) NC1. In addition, long-term inhibition of tumor growth was achieved by intermittent administration of hTERT/ RGD-alpha 3(IV) NC1. In conclusion, our findings demonstrate that tumor-specific antiangiogenic gene therapy utilizing RGD-alpha 3(IV) NC1 under the hTERT promoter inhibited angiogenesis in tumors, resulting in an antitumor effect.

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  • Coronary pressure measurement to identify the lesion requiring percutaneous coronary intervention in equivocal tandem lesions 国際誌

    M Hirota, K Iwasaki, K Yamamoto, S Kusachi, K Hina, S Hirohata, M Murakami, S Kamikawa, T Murakami, Y Shiratori

    CORONARY ARTERY DISEASE   17 ( 2 )   181 - 186   2006年3月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    No reliable methods are available for determining application of percutaneous coronary intervention for treatment of equivocal tandem lesions. We investigated whether coronary pressure measurement is useful for determining the lesion that requires percutaneous coronary intervention in tandem lesions.
    We measured coronary pressure in 72 consecutive patients with tandem lesions. Myocardial fractional flow reserve (FFRmyo) was obtained as the ratio of coronary pressure distal to the lesion/aortic pressure under maximal hyperemia. If the FFRmyo across the tandem lesions was &gt;= 0.75, we deferred percutaneous coronary intervention for the lesion. When the tandem lesions showed FFRmyo &lt; 0.75, percutaneous coronary intervention was performed on the lesion that showed angiographically higher stenosis. When FFRmyo was &lt; 0.75 after one-lesion percutaneous coronary intervention, this intervention was carried out on the remaining lesion.
    We deferred percuatneous coronary intervention for 26 patients (36.1%), and performed percutaneous coronary intervention in 46 patients (63.8%). We performed percutaneous coronary intervention for one lesion in 19 patients (26.4%) and for both lesions in 27 patients (37.5%). Among patients, in whom percutaneous coronary intervention was deferred, only two patients (7.7%) required target lesion revascularization during the follow-up period. This rate was not higher than that in the 46 patients who underwent percutaneous coronary intervention for one or two lesions (six patients, 13.0%). Similarly, the target lesion revascularization in lesions with initially deferred percuataneous coronary intervention (5.6%, 4/71 lesions) was not higher than that in lesions with percutaneous coronary intervention (15.1%, 11/73 lesions). Major cardiac events, cardiac death and acute myocardial infarction, did not occur in patients with deferred percutaneous coronary intervention during the follow-up period.
    Our results clearly showed that coronary pressure measurement was clinically useful for identifying equivocal tandem lesions requiring percutaneous coronary intervention.

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  • Nicorandil reduces the incidence of minor cardiac marker elevation after coronary stenting 国際誌

    M Murakami, K Iwasaki, S Kusachi, K Hina, M Hirota, S Hirohata, S Kamikawa, M Sangawa, K Yamamoto, Y Shiratori

    INTERNATIONAL JOURNAL OF CARDIOLOGY   107 ( 1 )   48 - 53   2006年2月

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    Background: Minor cardiac marker elevation after percutaneous coronary intervention has long-term prognostic significance. We examined whether nicorandil, a nicotinamide-nitrate ester, reduces the incidence of minor cardiac marker elevation after coronary stenting.
    Methods: Patients (n=192) undergoing coronary stenting were randomly assigned to receive nicorandil (nicorandil group, n=91) or vehicle (control group, n=101). Nicorandil (2 mu g/kg/min, intravenously) was administered immediately after the patients were transfer-red into the catheterization laboratory and continued for 6 h. We measured the serum concentrations of creatine kinase isoenzyme MB (CK-MB) before, immediately after, and 6, 12, and 24 h after the procedure, and those of cardiac troponin T (cTnT) 24 h after the procedure.
    Results: There was no significant difference in clinical background between the 2 groups. The nicorandil group showed a significantly lower incidence of CK-MB elevation (&gt; 1 x upper limit of control range, 20 IU/l) than the control group (8.8% vs 21.8%,p &lt; 0.05). The levels of serum CK-MB in the nicorandil group were significantly lower than those in the control group (13.4+5.7 vs 16.5 +/- 9.7 IU/l, p &lt; 0.01). Similarly, the nicorandil group showed a significantly lower incidence of cTnT elevation [&gt; 1 x (0.1 ng/ml) or &gt; 2x (0.2 ng/ml)] upper limit of control range than the control group (14.3% vs 26.7%, p &lt; 0.05, or 7.7% vs 17.8%,p &lt; 0.05). Serum cTnT levels were also significantly lower in the nicorandil group than in the control group (0.05 +/- 0.10 vs 0.15 +/- 0.36 ng/ml, p &lt; 0.05).
    Conclusions: The results demonstrated that nicorandil reduces minor cardiac marker elevation after coronary stenting. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

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  • Versican is induced in infiltrating monocytes in myocardial infarction 国際誌

    K Toeda, K Nakamura, S Hirohata, OF Hatipoglu, K Demircan, H Yamawaki, H Ogawa, S Kusachi, Y Shiratori, Y Ninomiya

    MOLECULAR AND CELLULAR BIOCHEMISTRY   280 ( 1-2 )   47 - 56   2005年12月

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    記述言語:英語   出版者・発行元:SPRINGER  

    Versican, a large chondroitin sulfate proteoglycan, plays a role in conditions such as wound healing and tissue remodelling. To test the hypothesis that versican expression is transiently upregulated and plays a role in the infarcted heart, we examined its expression in a rat model of myocardial infarction. Northern blot analysis demonstrated increased expression of versican mRNA. Quantitative real-time RT-PCR analysis revealed that versican mRNA began to increase as early as 6 h and reached its maximal level 2 days after coronary artery ligation. Versican mRNA then gradually decreased, while the mRNA of decorin, another small proteoglycan, increased thereafter. Versican mRNA was localized in monocytes, as indicated by CD68-positive staining, around the infarct tissue. The induction of versican mRNA was accelerated by ischemia/reperfusion (I/R), which was characterized by massive cell infiltration and enhanced inflammatory response. To examine the alteration of versican expression in monocytes/macrophages, we isolated human peripheral blood mononuclear cells and stimulated them with granulocyte/macrophage colony-stimulating factor (GM-CSF). Stimulation of mononuclear cells with GM-CSF increased the expression of versican mRNA as well as cytokine induction. The production of versican by monocytes in the infarct area represents a novel finding of the expression of an extracellular matrix gene by monocytes in the infarcted heart. We suggest that upregulation of versican in the infarcted myocardium may have a role in the inflammatory reaction, which mediates subsequent chemotaxis in the infarcted heart.

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  • Coronary pressure measurement to determine treatment strategy for equivocal left main coronary artery lesions

    S Suemaru, K Iwasaki, K Yamamoto, S Kusachi, K Hina, S Hirohata, M Hirota, M Murakami, S Kamikawa, T Murakami, Y Shiratori

    HEART AND VESSELS   20 ( 6 )   271 - 277   2005年11月

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    記述言語:英語   出版者・発行元:SPRINGER  

    It is often hard to select a treatment strategy for equivocal left main coronary artery (LMCA) disease. We investigated the usefulness of coronary pressure (CP) measurement for determining the treatment strategy in intermediate LMCA disease. We measured CP in 15 consecutive patients with equivocal LMCA disease (age 67.6 +/- 7.5 years, 14 males). Myocardial fractional flow reserve (FFRmyo) was obtained as the ratio of CP distal to the lesion/aortic pressure under maximal coronary dilation. Patients with FFRmyo &gt;= 0.75 and &lt; 0.75 received medical therapy and coronary artery bypass grafting (CABG), respectively, and were followed up for 32.5 +/- 9.7 (20-47) months. Eight patients received medical therapy and 7 patients underwent CABG in accordance with the FFRmyo criteria noted above. FFRmyo of the LMCA was 0.91 +/- 0.01 and 0.61 +/- 0.03 in patients who received medical and surgical therapy, respectively. Neither reference vessel diameter, minimal lumen diameter, nor percent diameter stenosis was significantly different between patients who received medical and surgical therapy. During the follow-up period, no patients with medical therapy showed symptoms due to the LMCA lesion. Similarly, 5 of 7 patients with CABG showed improvement of symptoms and the remaining 2 patients were hospitalized with congestive heart failure. No cardiac death was recorded in the patients with medical or surgical therapy. In conclusion, the present results clearly demonstrated that CP is clinically useful for determining the treatment strategy for equivocal LMCA lesions but coronary angiography is not.

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  • Thrombospondin-1 is induced in rat myocardial infarction and its induction is accelerated by ischemia/reperfusion 国際誌

    S Sezaki, S Hirohata, A Iwabu, K Nakamura, K Toeda, T Miyoshi, H Yamawaki, K Demircan, S Kusachi, Y Shiratori, Y Ninomiya

    EXPERIMENTAL BIOLOGY AND MEDICINE   230 ( 9 )   621 - 630   2005年10月

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    記述言語:英語   出版者・発行元:SOC EXPERIMENTAL BIOLOGY MEDICINE  

    Thrombospondin-1 (TSP-1) is a multifunctional, rapid-turnover matricellular protein. Recent studies demonstrated that TSP-1 has a role in regulating inflammatory reactions. Myocardial infarction (MI) is associated with an inflammatory response, ultimately leading to healing and scar formation. In particular, an enhanced inflammatory reaction and a massive accumulation of monocytes/macrophages is seen with reperfusion after MI. To examine the role of TSP-1 in MI, we isolated rat TSP-1 complementary DNA (cDNA) and analyzed the level and distribution of the mRNA expression. In infarcted rat hearts, TSP-1 mRNA increased markedly at 6 and 12 hrs after coronary artery ligation (27.97 +/- 3.40-fold and 22.77 +/- 1.83-fold, respectively, compared with sham-operated hearts). Western blot analysis revealed that TSP-1 protein was transiently induced in the infarcted heart. Using in situ hybridization analysis, TSP-1 mRNA signals were observed in the infiltrating cells at the border area of infarction. We then examined the effect of ischemia/reperfusion (I/R) on TSP-1 mRNA induction in the rats with infarcted hearts. Quantitative reverse transcriptase polymerase chain reaction (RT-PCR) demonstrated that I/R enhanced the TSP-1 mRNA expression approximately 4-fold, as compared with the level in the permanently ligated heart. Finally, we examined the effect of TSP-1 on proinflammatory cytokine release in mononuclear cells. The releases of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) from human mononuclear cells were enhanced by TSP-1 in a dose-dependent manner. Thus, the immediate and marked increase of TSP-1 expression suggests that TSP-1 has an inflammatory-associated role in MI.

    DOI: 10.1177/153537020523000904

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  • Frequent deletion and down-regulation of ING4, a candidate tumor suppressor gene at 12p13, in head and neck squamous cell carcinomas 国際誌

    M Gunduz, H Nagatsuka, K Demircan, E Gunduz, B Cengiz, M Ouchida, H Tsujigiwa, E Yamachika, K Fukushima, L Beder, S Hirohata, Y Ninomiya, K Nishizaki, K Shimizu, N Nagai

    GENE   356 ( 1-2 )   109 - 117   2005年8月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE BV  

    We previously showed two members of the ING family, ING1 and ING3 as a tumor suppressor gene in head and neck cancer. Progress in human genome sequencing provided additional information of the new members of the ING family genes. ING4 is localized to chromosome 12p13.31 region and harbors the PHD domain highly homologous among ING family proteins. We analyzed loss of heterozygosity at 12p12-13 region in 50 head and neck squamous cell carcinomas by using six highly polymorphic microsatellite markers and found allelic loss in 66% (33/50) of the informative cases. To clarify the role of ING4 in head and neck carcinogenesis, we first checked mutation status in tumor samples. As mutation of the ING4 gene was not found in head and neck cancers, we examined the mRNA expression level. Quantitative real-time RT-PCR analysis demonstrated decreased expression of ING4 mRNA in 76% of primary tumors as compared with that of matched normal samples. Since p53 dependent pathways of other ING family members have been shown, we examined p53 mutation status and compared with ING4 mRNA expression in tumor samples. However, no such direct relationship has been detected. In conclusion, frequent deletion and decreased mRNA expression of ING4 suggested it as a class two tumor suppressor gene and may play an important role in head and neck cancer. (c) 2005 Elsevier B.V. All rights reserved.

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  • Therapeutic efficacy of PUMA for malignant glioma cells regardless of p53 status 国際誌

    H Ito, T Kanzawa, T Miyoshi, S Hirohata, S Kyo, A Iwamaru, H Aoki, Y Kondo, S Kondo

    HUMAN GENE THERAPY   16 ( 6 )   685 - 698   2005年6月

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    記述言語:英語   出版者・発行元:MARY ANN LIEBERT INC  

    Replacement of the p53 tumor suppressor gene is a rational approach to the management of malignant gliomas because p53 is frequently mutated or inactivated in these cancers. Major weaknesses of this approach are that malignant gliomas are mixtures of cells with wild- type and mutant p53, and that tumor cells exhibiting wildtype p53 are resistant to p53 gene transfer. An effective alternative is needed to overcome these difficulties. p53-upregulated modulator of apoptosis ( PUMA) was identified as a p53- inducible proapoptotic molecule. Our purpose was to elucidate a role for PUMA in p53 gene therapy and to investigate whether PUMA is an efficient substitute for p53 in cancer therapy. We demonstrated that PUMA was upregulated in mutant p53 malignant glioma cells (U373-MG and T98G) undergoing apoptosis but was not upregulated in apoptosis-resistant wild- type p53 malignant glioma cells (U87-MG and D54) after adenoviral transfer of p53. Overexpression of PUMA resulted in massive apoptosis associated with mitochondrial damage and caspase-3 activation in all tumor cells tested. Use of the human telomerase reverse transcriptase ( hTERT) promoter system induced apoptosis only in malignant glioma cells with telomerase activity, while sparing normal cells lacking telomerase. The ability of PUMA to induce apoptosis was greater than that of caspase-6 or caspase-8 transfer, using the same system. Moreover, exogenous expression of PUMA under the hTERT promoter system significantly suppressed the growth of subcutaneous U87-MG tumors in nude mice and did not induce apoptosis in surrounding nontumor tissues. These results indicate that PUMA, which is regulated under a tumor-specific expression system such as the hTERT promoter, may be better than p53 as a therapeutic tool for malignant gliomas.

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  • Significant correlation of recruitable coronary collateral blood flow determined by coronary wedge pressure with ST-segment elevation during coronary occlusion 国際誌

    S Karnikawa, K Iwasaki, K Yamamoto, S Kusachi, K Hina, S Hirohata, M Murakami, M Hirota, T Murakami, Y Shiratori

    CORONARY ARTERY DISEASE   16 ( 4 )   231 - 236   2005年6月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Objectives Quantitative assessment of coronary collateral blood flow can be archived by measuring coronary pressure. We studied the relationships between recruitable coronary collateral blood flow and electrocardiographic changes during percutaneous coronary intervention (PCI).
    Methods We measured coronary pressure during coronary occlusion with PCI in 119 patients with left anterior descending coronary artery stenosis. During balloon inflation, the electrocardiogram was continuously recorded. The ST-segment elevation in the most elevated lead was defined as MaxST and the sum of the maximal ST elevation in leads V2-V4 was defined as Sigma ST. Fractional collateral flow (Qc/Q(N)) was calculated as the coronary wedge pressure divided by the mean aortic pressure. Myocardial ischemia was defined as an ST-segment shift &gt; 0.1 mV in any of the V2, V3 or V4 leads.
    Results A significant relationship between Qc/Q(N) and MaxST was observed (r= -0.455, P &lt; 0.0001). Similarly, Qc/Q(N) was significantly correlated with Sigma ST (r= - 0.477, P &lt; 0.0001). The receiver operating characteristic curve showed that a cut-off value of 0.27 for Qc/Q(N), with sensitivity of 71.4% and specificity of 76.2%, was an indicator of electrophysiologically sufficient recruitable coronary collateral blood flow for prevention of ischemia during coronary obstruction. Qc/Q(N) values during the first, second, third and fourth inflation were not significantly different.
    Conclusions Qc/Q(N) could be clinically useful for determining whether there is electrophysiologically sufficient recruitable coronary collateral blood flow for prevention of ischemia during coronary obstruction. Repeat transient coronary occlusion during PCI did not lead to increased collateral blood flow. (c) 2005 Lippincott Williams & Wilkins.

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  • ADAMTS-9 is synergistically induced by interleukin-1 beta and tumor necrosis factor alpha in OUMS-27 chondrosarcoma cells and in human chondrocytes 国際誌

    K Demircan, S Hirohata, K Nishida, OF Hatipoglu, T Oohashi, T Yonezawa, SS Apte, Y Ninomiya

    ARTHRITIS AND RHEUMATISM   52 ( 5 )   1451 - 1460   2005年5月

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    記述言語:英語   出版者・発行元:WILEY-LISS  

    Objective. To compare induction of the aggrecanases (ADAMTS-1, ADAMTS-4, ADAMTS-5, ADAMTS-8, ADAMTS-9, and ADAMTS-15) by interleukin-1&beta; (IL-1&beta;) and tumor necrosis factor a (TNF&alpha;) in chondrocyte-like OUMS-27 cells and human chondrocytes, and to determine the mechanism of induction of the most responsive aggrecanase gene.
    Methods. OUMS-27 cells were stimulated for different periods of time and with various concentrations of IL-1&beta; and/or TNFa. Human chondrocytes obtained from osteoarthritic joints and human skin fibroblasts were also stimulated with IL-1&beta; and/or TNF&alpha;. Total RNA was extracted, reverse transcribed, and analyzed by quantitative real-time polymerase chain reaction and Northern blotting. ADAMTS-9 protein was examined by Western blotting, and the role of the MAPK signaling pathway for ADAMTS9 induction in IL-1&beta;-stimulated OUMS-27 cells was investigated.
    Results. IL-1&beta; increased messenger RNA (mRNA) levels of ADAMTS4, ADAMTS5, and ADAMTS9 but not ADAMTS1 and ADAMTS8. The fold increase for ADAMTS9 mRNA was greater than that for mRNA of the other aggrecanase genes. The increase of ADAMTS9 mRNA by IL-1&beta; stimulation was greater in chondrocytes than in fibroblasts. The combination of IL-1&beta; and TNF&alpha; had a synergistic effect, resulting in a considerable elevation in the level of ADAMTS9 mRNA. ADAMTS-9 protein was also induced in IL-1&beta;-stimulated OUMS-27 cells. The MAPK inhibitors SB203580 and PD98059 decreased ADAMTS9 upregulation in OUMS-27 cells.
    Conclusion. ADAMTS9 is an IL-1&beta;- and TNF&alpha;-inducible gene that appears to be more responsive to these proinflammatory cytokines than are other aggrecanase genes. Furthermore, these cytokines had a synergistic effect on ADAMTS9. Together with the known ability of ADAMTS-9 to proteolytically degrade aggrecan and its potential to cleave other cartilage molecules, the data suggest that ADAMTS-9 may have a pathologic role in arthritis.

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  • Suppression of chondrosarcoma cells by 15-deoxy-Delta (12,14)-prostaglandin J(2) is associated with altered expression of Bax/Bcl-xL and p21 国際誌

    ZN Shen, K Nishida, H Doi, T Oohashi, S Hirohata, T Ozaki, A Yoshida, Y Ninomiya, H Inoue

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   328 ( 2 )   375 - 382   2005年3月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    We previously reported that 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), the most potent agonist for peroxisome proliferator-activated receptor gamma (PPARgamma), induces apoptosis of human chondrosarcoma cell line OUMS-27. The current study aimed to explore the mechanism of 15d-PGJ(2)-induced apoptosis and inhibition of cell proliferation in OUMS-27 cells. The preliminary results of cDNA microarray analysis showed the down-regulation of anti-apoptotic Bcl-xL and up-regulation of pro-apoptotic Bax in the process of 15d-PGJ2-induced apoptosis. These changes were further confirmed at mRNA and protein levels by RT-PCR and Western blot analysis, respectively. Among cyclin-dependent kinase inhibitors, p21 was induced and up-regulated by 15d-PGJ2, but p 16 and p27 were not changed, suggesting that the involvement of p21 in inhibition of cell proliferation. Activation of caspase-3 by 15d-PGJ2 was partly, but not completely, blocked by PPARgamma antagonist (GW9662) suggesting the 15d-PGJ2 exerted its effect by PPARgamma-dependent and -independent pathways. Interestingly, immunohistochemical study on human chondrosarcoma samples revealed that Bcl-xL is frequently expressed by tumor cells. The results of the current study suggest that the potential ability of 15d-PGJ2 in regulation of cell cycle and inhibition of Bcl-xL expression might be beneficial in the development of novel pharmacological agents for chondrosarcoma. (C) 2005 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.bbrc.2004.12.186

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  • Time-dependent changes in plasma osteopontin levels in patients with anterior-wall acute myocardial infarction after successful reperfusion: Correlation with left-ventricular volume and function 国際誌

    C Suezawa, S Kusachi, T Murakami, K Toeda, S Hirohata, K Nakamura, K Yamamoto, K Koten, T Miyoshi, Y Shiratori

    JOURNAL OF LABORATORY AND CLINICAL MEDICINE   145 ( 1 )   33 - 40   2005年1月

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    記述言語:英語   出版者・発行元:MOSBY, INC  

    Osteopontin Is a secreted extracellular-matrix glycoprotein that plays a role in the healing of remodeling tissue. We examined the relationship of plasma osteopontin levels with left-ventricular (LV) volume and function In 18 consecutive patients who underwent successful reperfusion after anterior-wall acute myocardial Infarction (AMI). The plasma osteopontin level was within the control range at admission (mean +/- SD 420 +/- 195 ng/mL), began to Increase on day 2 (935 +/- 464 ng/mL), and reached a maximum around day 3 (1139 482 ng/mL). The level remained high on days 4, 5, and 7 (similar to1000 ng/mL) and then decreased on day 14. Maximal plasma osteopontin levels and the difference between maximal and minimal levels were positively correlated with LV end-systolic volume index (r = .58, P &lt; .05; and r = .65, P &lt; .01, respectively) and negatively correlated with LV election fraction (r = -.52, P &lt; .05; and r = -.60, P &lt; .01, respectively). The area under the curve of plasma osteopontin levels for 14 days after AMI was significantly correlated with LV end-systolic volume index (r = .66, P &lt; .01), LV end-diastolic volume index (r = .50, P &lt; .05), and LV ejection fraction (r = -.55, P &lt; .05). In subgroup patients with the same area of risk for myocardial infarction (ie, responsible lesions located at the same proximal left anterior descending coronary artery), essentially the some or a closer relationship between plasma osteopontin level and LV volume and function was noted. Plasma osteopontin levels were correlated substantially with plasma levels of high-sensitivity C-reactive protein (hsCRP) and weakly with serum creatine kinase release. In conclusion, the plasma level of osteopontin changes In a time-dependent fashion and Is correlated with LV volumes and function and associated substantially with the extent of the Inflammatory response Indicated by the plasma hsCRP level and weakly with Infarct size estimated on the basis of cardiac-enzyme release.

    DOI: 10.1016/j.lab.2004.08.007

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  • 5) Identification and Characterization of a novel rat link protein gene : Lp3/Hapln3(第84回日本循環器学会中国地方会)

    小川 弘子, 廣畑 聡, 三好 亨, 村上 充, 白鳥 康史, 大橋 俊孝, 二宮 善文, 草地 省蔵, 佐田 政隆

    Circulation journal : official journal of the Japanese Circulation Society   68 ( 0 )   2004年10月

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    記述言語:日本語   出版者・発行元:社団法人日本循環器学会  

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  • Dynamic induction of ADAMTS1 gene in the early phase of acute myocardial infarction 国際誌

    K Nakamura, S Hirohata, T Murakami, T Miyoshi, K Demircan, T Oohashi, H Ogawa, K Koten, K Toeda, S Kusachi, Y Ninomiya, Y Shiratori

    JOURNAL OF BIOCHEMISTRY   136 ( 4 )   439 - 446   2004年10月

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    記述言語:英語   出版者・発行元:JAPANESE BIOCHEMICAL SOC  

    Extracellular matrix (ECM)-degrading enzymes such as matrix metalloproteases (MMPs) play an essential role in the repair of infarcted tissue, which affects ventricular remodeling after myocardial infarction. ADAMTS1 (A disintegrin and metalloprotease with thrombospondin motifs), a newly discovered metalloprotease, was originally cloned from a cancer cell line, but little is known about its contribution to disease. To test the hypothesis that ADAMTS1 appears in infarcted myocardial tissue, we examined ADAMTS1 mRNA expression in a rat myocardial infarction model by Northern blotting, real-time RT-PCR and in situ hybridization. Normal endothelium expressed little ADAMTS1 mRNA, while normal myocardium expressed no detectable ADAMTS1 mRNA. Up-regulation of ADAMTS1 was demonstrated by Northern blot analysis and real-time RT-PCR at 3 h after coronary artery ligation. In situ hybridization revealed strong ADAMTS1 mRNA signals in the endothelium and myocardium in the infarcted heart, mainly in the infarct zone, at 3 h after myocardial infarction. The rapid and transient up-regulation of the ADAMTS1 gene in the ischemic heart was distinct from the regulatory patterns of other MMPs. Our study demonstrated that the ADAMTS1 gene is a new early immediate gene expressed in the ischemic endothelium and myocardium.

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  • Lp3/Hapln3, a novel link protein that co-localizes with versican and is coordinately up-regulated by platelet-derived growth factor in arterial smooth muscle cells 国際誌

    H Ogawa, T Oohashi, M Sata, Y Bekku, S Hirohataa, K Nakamura, T Yonezawa, S Kusachi, Y Shiratori, Y Ninomiya

    MATRIX BIOLOGY   23 ( 5 )   287 - 298   2004年8月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE BV  

    Link proteins (LPs) belong to the link-module superfamily, which can stabilize and enhance the binding of lecticans to hyaluronan. We report here the identification and characterization of a novel rat link protein gene (Lp3/Hapln3). The deduced protein sequence shares the typical modular elements of link proteins and has an estimated mass of 39 kDa. Examination of the rat genomic DNA sequence revealed that Lp3/ Hapln3 and aggrecan genes were paired on chromosome 1q31. Another LP gene and the lectican gene were also paired at a different locus, as they are in the human and mouse genomes. Immunohistochemical analysis showed the prominent expression of Lp3/Hapln3 in the smooth muscle tissues of the vascular wall and gastrointestinal tract. Further comparative studies revealed that Lp3/Hapln3 was well co-localized with versican around the smooth muscle cells of blood vessels but not around endothelial cells. In vitro experiments using primary cultured rat arterial smooth muscle cells (ASMCs) demonstrated the coordinated up-regulation of Lp3/Hapln3 and versican by platelet-derived growth factor (PDGF). These data were supported by in vivo studies of a mechanical vascular injury model in mice. Altogether, our results suggest that Lp3/Hapln3 is involved, together with versican and hyaluronan, in the formation of the pericellular matrix of vascular smooth muscle cells. (C) 2004 Elsevier B.V./International Society of Matrix Biology. All rights reserved.

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  • Combination of caspase transfer using the human telomerase reverse transcriptase promoter and conventional therapies for malignant glioma cells 国際誌

    H Takeuchi, T Kanzawa, Y Kondo, T Komata, S Hirohata, S Kyo, S Kondo

    INTERNATIONAL JOURNAL OF ONCOLOGY   25 ( 1 )   57 - 63   2004年7月

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    記述言語:英語   出版者・発行元:PROFESSOR D A SPANDIDOS  

    Recently, we have reported the therapeutic efficacy of delivering initiator caspase (caspase-8) or executioner active caspase (rev-caspase-6) to telomerase-positive malignant glioma cells using the human telomerase reverse transcriptase (hTERT) gene promoter system (hTERT/caspase-8 or hTERT/rev-caspase-6). In the present study, we investigated if conventional treatments for malignant gliomas augment the efficacy of the hTERT/caspase therapy. First, we demonstrated that hTERT/rev-caspase-6 exhibited a greater ability to induce apoptosis in malignant glioma U87-MG and U373-MG cells than hTERT/caspase-8. Next, as conventional treatments to combine with hTERT/rev-caspase-6, apoptosis-inducing agents [cisplatin (CDDP), paclitaxel (PTX), and BCNU] and non-apoptosis-inducing therapies [temozolomide (TMZ) and gamma-irradiation (IR)] were used. Combination of hTERT/rev-caspase-6 gene therapy with PTX yielded a dose-dependent additive effect, while CDDP and BCNU had additive effect only when tumor cells were treated at IC75 of each agent. A decline in the combination effect of CDDP and BCNU at IC50 was due to decreased activity of telomerase in treated tumor cells prior to the hTERT/rev-caspase-6 transfer. On the other hand, TMZ or IR had no significant additive effect on induction of apoptosis. These results suggest that agents, which induce apoptosis without inhibiting telomerase activity are a promising counterpart to combine with hTERT/rev-caspase-6 therapy for the management of malignant gliomas.

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  • Spatially and temporally different expression of osteonectin and osteopontin in the infarct zone of experimentally induced myocardial infarction in rats

    Komatsubara, I, T Murakami, S Kusachi, K Nakamura, S Hirohata, J Hayashi, S Takemoto, C Suezawa, Y Ninomiya, Y Shiratori

    CARDIOVASCULAR PATHOLOGY   12 ( 4 )   186 - 194   2003年7月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE INC  

    Osteonectin and osteopontin, two secreted matricellular proteins, have a variety of functions that are exerted through interaction with matrix components. These proteins appear in response to tissue injury. To test our hypothesis that osteopontin and osteonectin are expressed with spatially and temporally different patterns in myocardial infarct tissue, we investigated osteonectin and osteopontin expression in experimentally induced myocardial infarction in rats, in comparison with Type I collagen expression. Northern blotting demonstrated that osteonectin mRNA did not markedly increase on Day 2 after the infarction, but it increased on Days 7 and 14 by 1.7 +/- 0.12- and 1.8 +/- 0.01-fold compared to that in preligation hearts. In contrast, osteopontin mRNA was increased on Day 1 (41.9 +/- 11.3-fold increase) and on Day 2 (58.3 +/- 7.6-fold increase), and then it declined on Days 7 and 14 (24.8 +/- 9.0- and 13.5 +/- 4.7-fold increase, respectively). In situ hybridization revealed that osteonectin mRNA signals were observed in fibroblasts, myofibroblasts and macrophages around infarct necrotic tissue on Days 7 and 14. Osteopontin mRNA signals were observed in macrophages in the infarct marginal zone on Day 2. Immunopositive staining for both osteonectin and osteopontin showed the same pattern as that obtained by in situ hybridization. The time course of osteonectin mRNA was almost parallel with that of Type I collagen mRNA, while that of osteopontin was not. These results demonstrated spatially and temporally different expression patterns of osteonectin and osteopontin in myocardial infarction and suggest that osteonectin appears to be involved in the pathological course in the late phase after infarction concomitantly with Type I collagen, while osteopontin may play a role in the early phase. (C) 2003 Elsevier Inc. All rights reserved.

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  • 胆嚢炎に続発した感染性腹部大動脈瘤の一例

    三好亨, 広畑敦, 小天和也, 土井正行, 廣畑 聡, 瀬崎悟之, 村上充, 草地省蔵, 白鳥康史

    Circulation Journal   2003年

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  • Increased expression of dermatopontin mRNA in the infarct zone of experimentally induced myocardial infarction in rats: comparison with decorin and type I collagen mRNAs 国際誌

    S Takemoto, T Murakami, S Kusachi, A Iwabu, S Hirohata, K Nakamura, S Sezaki, J Hayashi, C Suezawa, Y Ninomiya, T Tsuji

    BASIC RESEARCH IN CARDIOLOGY   97 ( 6 )   461 - 468   2002年11月

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    記述言語:英語   出版者・発行元:DR DIETRICH STEINKOPFF VERLAG  

    Objectives Dermatopontin, a 22 kDa extracellular matrix (ECM) protein, has been shown to interact with other ECM components, especially decorin, and to regulate ECM formation. We examined dermatopontin mRNA expression in the myocardial infarct zone. Methods The cDNA encoding the rat dermatopontin was cloned by RT-PCR based on screening results from the Expressed Sequence Tag(TM) database. The dermatopontin mRNA expression was examined in the infarct zone after experimentally induced myocardial infarction in rats by the methods of Northern blotting and in situ hybridization. The expression of dermatopontin mRNA was compared to that of decorin and type I collagen mRNAs. Results The isolated clone contained a 609 bp cDNA insert containing a complete open reading frame encoding 202 amino acids. The rat dermatopontin cDNA showed high homology to human and mouse counterparts (&gt;96%). Northern blotting demonstrated that dermatopontin mRNA expression did not markedly increase on day 2, but was increased on days 7, 14 and 28 by 2.4-, 4.1- and 4.2-fold, respectively, compared to that in preligation hearts. Dermatopontin mRNA expression was regulated almost in parallel with decorin mRNA expression. In situ hybridization demonstrated mRNA signals for dermatopontin in macrophages and spindle-shaped mesenchymal cells (fibroblasts and myofibroblasts) located in the infarct interior zone around infarcted necrotic tissue on day 7. Coexpression of dermatopontin mRNA with decorin and type I collagen mRNAs was observed in spindle-shaped mesenchymal cells. Conclusions The present results demonstrated the time-dependent increase in the expression of dermatopontin mRNA in parallel with that of decorin mRNA in the infarct zone. Coexpression of dermatopontin mRNA with decorin and type I collagen mRNAs suggests that dermatopontin plays a role in ECM (fibrillar collagen matrix) reformation in the infarct along with decorin and type I collagen.

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  • Caspase-8 gene therapy using the human telomerase reverse transcriptase promoter for malignant glioma cells 国際誌

    T Komata, Y Kondo, T Kanzawa, H Ito, S Hirohata, S Koga, H Sumiyoshi, M Takakura, M Inoue, BP Barna, EM Germano, S Kyo, S Kondo

    HUMAN GENE THERAPY   13 ( 9 )   1015 - 1025   2002年6月

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    記述言語:英語   出版者・発行元:MARY ANN LIEBERT INC PUBL  

    Telomerase is a distinctive candidate for targeted gene therapy of malignant gliomas, because the vast majority of malignant gliomas express telomerase activity while normal brain tissues do not. Recently, we developed a telomerase-specific expression system of caspase-8 gene using the promoter of the human telomerase reverse transcriptase (hTERT) gene. However, the transcriptional activity of hTERT-181 promoter (a 181-base pair [bp] region upstream of the transcription start site) was relatively lower in malignant glioma cells than in other tumors such as prostate cancer cells. To establish the hTERT/caspase-8 construct as a novel therapy for malignant gliomas, we need to increase the transcriptional activity of the hTERT promoter in malignant glioma cells. In the present study, we demonstrate that the transcriptional activity of hTERT-378 promoter (a 378-bp region) was 2- to 40-fold higher in hTERT-positive malignant glioma cells (A172, GB-1, T98G, U87-MG, U251-MG, and U373-MG) than that of hTERT-181. We further demonstrate that by using the hTERT-378/caspase-8 construct, apoptosis was restricted to malignant glioma cells, and was not seen in astrocytes or fibroblasts lacking hTERT. Moreover, the growth of subcutaneously established U373-MG tumors in mice was significantly inhibited by seven daily intratumoral injections of hTERT-378/caspase-8 construct and its inhibitory effect persisted during 3 additional weeks without additional treatment. These results suggest that the telomerase-specific expression of caspase-8 under hTERT-378 promoter is a novel targeting approach for the treatment of telomerase-positive malignant gliomas.

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  • Punctin, a novel ADAMTS-like molecule, ADAMTSL-1, in extracellular matrix 国際誌

    S Hirohata, LW Wang, M Miyagi, L Yan, MF Seldin, DR Keene, JW Crabb, SS Apte

    JOURNAL OF BIOLOGICAL CHEMISTRY   277 ( 14 )   12182 - 12189   2002年4月

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    記述言語:英語   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    Punctin (ADAMTSL-1) is a secreted molecule resembling members of the ADAMTS family of proteases. Punctin lacks the pro-metalloprotease and the disintegrin-like domain typical of this family but contains other ADAMTS domains in precise order including four thrombospondin type I repeats. Punctin is the product of a distinct gene on human chromosome 9p21-22 and mouse chromosome 4 that is expressed in adult skeletal muscle. His-tagged punctin expressed in stably transfected High-Five(TM) insect cells was purified to apparent homogeneity by Ni-chromatography of conditioned medium. The NH2 terminus is not blocked and has the sequence EEDRD and so forth as determined by Edman degradation, demonstrating signal peptidase processing. Recombinant epitope-tagged punctin has a calculated mass of 59,991 Da but exhibits major molecular species of 61970 +/- 6 Da and 62131 +/- 5 Da as measured by liquid chromatography electrospray mass spectrometry. Punctin is a glycoprotein based on carbohydrate staining and liquid chromatography electrospray mass spectrometry glycopeptide analysis. Glycosylation occurs at a single N-linked site as demonstrated by altered electrophoretic migration of punctin expressed in the presence of tunicamycin A. Punctin contains disulfide bonds based on antibody accessibility and electrophoretic migration under reducing versus nonreducing conditions. Rotary shadowing demonstrates that punctin is hatchet-shaped having a globular region attached to a short stem. In transfected COS-1 cells, punctin is deposited in the cell substratum in a punctate fashion and is excluded from focal contacts. Punctin is the first member of a novel family of ADAMTS-like proteins that may have important functions in the extracellular matrix.

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  • A novel treatment of human malignant gliomas in vitro and in vivo: FADD gene transfer under the control of the human telomerase reverse transcriptase gene promoter

    T Komata, S Koga, S Hirohata, M Takakura, IM Germano, M Inoue, S Kyo, S Kondo, Y Kondo

    INTERNATIONAL JOURNAL OF ONCOLOGY   19 ( 5 )   1015 - 1020   2001年11月

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    記述言語:英語   出版者・発行元:PROFESSOR D A SPANDIDOS  

    Telomerase activity has a close relationship with malignancies in many cell types and it is tightly regulated at the transcriptional level of human telomerase reverse transcriptase (hTERT). Utilizing the hTERT promoter, the authors developed a gene delivery system of Fas associated protein with death domain (FADD) (hTERT/FADD). FADD is a protein which plays an important role in the apoptotic pathway of Fas. Overexpression of FADD induces apoptosis in the cells regardless of Fas expression on the cell surface. We hypothesized that we might be able to restrict the expression of FADD in malignant glioma cells if we use the gene transfer system under the control of hTERT promoter. This study was designed to investigate whether the hTERT/FADD construct induces apoptosis effectively in malignant glioma cells while keeping normal cells intact. First, using the reverse transcription-polymerase chain reaction (RT-PCR) technique, we confirmed that hTERT mRNA was expressed in human malignant glioma cells (U373-MG, A172 and GB-1), but not in cultured astrocytes (TEN) or fibroblasts (MRC5). After transient transfection with the hTERT/FADD construct, a significant number of FADD-positive cells and apoptotic cells were detected in hTERT-positive malignant glioma cells. In contrast, hTERT-negative astrocytes and fibroblasts remained intact. Furthermore, subcutaneously implanted U373-MG tumors treated with the hTERT/FADD construct reduced in volume significantly C compared to the conrol treatment (p=0.0001). Gene transfer of FADD under the control of the hTERT promoter may be a novel and promising therapy to kill hTERT-positive malignant glioma cells while sparing normal brain cells lacking hTERT.

    DOI: 10.3892/ijo.19.5.1015

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  • Increased expression of biglycan mRNA in pressure-overloaded rat heart

    Y Ayada, S Kusachi, T Murakami, S Hirohata, S Takemoto, Komatsubara, I, J Hayashi, A Iwabu, Y Ninomiya, T Tsuji

    CLINICAL AND EXPERIMENTAL HYPERTENSION   23 ( 8 )   633 - 643   2001年11月

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    記述言語:英語   出版者・発行元:MARCEL DEKKER INC  

    Biglycan mRNA expression in rat myocardium after abdominal aortic banding with renal ischemia was examined. The Northern blot analysis demonstrated that expression of biglycan mRNA in the pressure-overloaded hearts on days 2, 7, 14 and 28 was 2.88 +/-0.89, 2.32 +/-0.49, 2.17 +/-0.57 and 1.81 +/-0.46-fold higher, respectively, than that in the sham-operated hearts. In situ hybridization showed an increased density of biglycan mRNA signal-positive cells in the pressure-overloaded hearts. The cells with positive signals were spindle-shaped mesenchymal cells in the myocardial interstitium. A marked increase in biglycan mRNA signal expression was also observed in endothelial cells and smooth muscle cells of the thickened myocardial capillary wall. These results demonstrated an increase in biglycan mRNA in the pressure-overloaded heart in mesenchymal cells in the myocardial interstitium, and in endothelial and smooth muscle cells of the capillaries, indicating that biglycan contributes to the ventricular and vascular remodeling in response to pressure overload.

    DOI: 10.1081/CEH-100107393

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  • Treatment of malignant glioma cells with the transfer of constitutively active caspase-6 using the human telomerase catalytic subunit (human telomerase reverse transcriptase) gene promoter

    T Komata, Y Kondo, T Kanzawa, S Hirohata, S Koga, H Sumiyoshi, SM Srinivasula, BP Barna, IM Germano, M Takakura, M Inoue, ES Alnemri, JW Shay, S Kyo, S Kondo

    CANCER RESEARCH   61 ( 15 )   5796 - 5802   2001年8月

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    記述言語:英語   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Because the apoptotic pathway is often disrupted in tumor cells, its genetic restoration is a very attractive approach for the treatment of tumors. To treat malignant gliomas with this approach, it would be preferred to restrict induction of apoptosis to tumor cells by establishing a tumor-specific expression system. Telomerase is an attractive target because the vast majority of malignant gliomas have telomerase activity whereas normal brain cells do not. Activation of telomerase is tightly regulated at the transcriptional level of the telomerase catalytic subunit [human telomerase reverse transcriptase, (hTERT)]. Therefore, we hypothesized that using a hTERT promoter-driven vector system, an apoptosis-inducible gene may be preferentially restricted to telomerase- or hTERT-positive tumor cells. In this study, we constructed an expression vector consisting of the constitutively active caspase-6 (rev-caspase-6) under the hTERT promoter (hTERT/rev-caspase-6) and then investigated its antitumor effect on malignant glioma cells. The rationale for using the rev-caspase-6 gene is because it induces apoptosis independent of the initiator caspases. We demonstrated that the hTERT/rev-caspase-6 construct induced apoptosis in hTERT-positive malignant glioma cells, but not in hTERT-negative astrocytes, fibroblasts, and alternative lengthening of telomeres cells. In addition, the growth of s.c. tumors in nude mice was significantly suppressed by the treatment with hTERT/rev-caspase-6 construct. The present results strongly suggest that the telomerase-specific transfer of the rev-caspase-6 gene under the hTERT promoter is a novel targeting approach for the treatment of malignant gliomas.

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  • Procollagen II amino propeptide processing by ADAMTS-3 - Insights on dermatosparaxis

    RJ Fernandes, S Hirohata, JM Engle, A Colige, DH Cohn, DR Eyre, SS Apte

    JOURNAL OF BIOLOGICAL CHEMISTRY   276 ( 34 )   31502 - 31509   2001年8月

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    記述言語:英語   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    The amino and carboxyl propeptides of procollagens I and Il are removed by specific enzymes as a prerequisite for fibril assembly. Null mutations in procollagen I N-propeptidase (ADAMTS-2) cause dermatosparaxis in cattle and the Ehlers-Danlos syndrome (dermatosparactic type) in humans by preventing proteolytic excision of the N-propeptide of procollagen I. We have found that procollagen II is processed normally in dermatosparactic nasal cartilage, suggesting the existence of another N-propeptidase(s). We investigated such a role for ADAMTS-3 in Swarm rat chondrosarcoma RCS-LTC cells, which fail to process the procollagen II N-propeptide. Stable transfection of RCS-LTC cells with bovine ADAMTS-2 or human ADAMTS-3 partially rescued the, processing defect, suggesting that ADAMTS-3 has procollagen II N-propeptidase activity. Human skin and skin fibroblasts showed 30-fold higher mRNA levels of ADAMTS-2 than ADAMTS-3, whereas ADAMTS-3 mRNA was 5-fold higher than ADAMTS-2 mRNA in human cartilage. We propose that both ADAMTS-2 and ADAMTS-3 process procollagen II, but ADAMTS-3 is physiologically more relevant, given its preferred expression in cartilage. The findings provide an explanation for the sparing of cartilage in dermatosparaxis and, perhaps, for the relative sparing of some procollagen I-containing tissues.

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  • FADD gene therapy using the human telomerase catalytic subunit (hTERT) gene promoter to restrict induction of apoptosis to tumors in vitro and in vivo

    S Koga, S Hirohata, Y Kondo, T Komata, M Takakura, M Inoue, S Kyo, S Kondo

    ANTICANCER RESEARCH   21 ( 3B )   1937 - 1943   2001年5月

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    記述言語:英語   出版者・発行元:INT INST ANTICANCER RESEARCH  

    Gene transfer vectors will dramatically increase the safety and effectiveness of cancer gene therapy, if they could restrict expression of the therapeutic products to the target tumors. To realize such a tumor-targeting system, telomerase is one of the most promising candidates. It is because telomerase activity is detected in the vast majority of tumors, but not in most normal cells. Activation of telomerase is tightly regulated at the transcriptional level of the telomerase catalytic subunit (hTERT). Therefore, the use of the hTERT promoter-driven vector system could restrict the expression of therapeutic products to telomerase positive tumors. In this study, we constructed the expression vector of FADD gene with death domain afforded by the hTERT promoter (hTERT/FADD) and investigated its effect on tumors in vitro and in vivo. Transient transfection with the hTERT/FADD construct induced apoptosis in telomerase-positive tumor cells of wide range. In contrast, normal fibroblast cells without telomerase did not undergo apoptosis following the hTERT/FADD transfer. Furthermore, the growth of subcutaneous tumors in nude mice was significantly suppressed by the intratumoral injection of the hTERT/FADD construct (every day for one week) compared to the control (P &lt;0.0005). The findings described here indicate the high potentiality of a novel telomerase-specific gene therapy of tumors with telomerase.

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  • 新しい細胞外マトリックス分解酵素ADAMTSファミリー

    廣畑 聡

    生化学   73,11,1333-1337   2001年

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  • A novel telomerase-specific gene therapy: Gene transfer of caspase-8 utilizing the human telomerase catalytic subunit gene promoter

    Shoji Koga, Satoshi Hirohata, Yasuko Kondo, Tadashi Komata, Masahiro Takakura, Masaki Inoue, Saturo Kyo, Seiji Kondo

    Human Gene Therapy   11 ( 10 )   1397 - 1406   2000年7月

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    記述言語:英語  

    Apoptosis is a genetically encoded cell death process and is a pathway that may be disrupted in tumor cells. Therefore, therapies that restore the ability to undergo apoptosis are promising for the treatment of tumor cells. We have demonstrated that the transfer of apoptosis-inducible genes inhibits the growth of tumors in vitro and in vivo through induction of apoptosis. However, to restrict induction of apoptosis to tumor cells, we need to explore a tumor-specific expression system of these genes. In the present study, we developed the telomerase-specific transfer system of apoptosis- inducible genes, utilizing the promoter of the human telomerase catalytic subunit (hTERT) gene. Approximately 90% of tumors have telomerase activity whereas most normal cells do not express the activity. These observations indicate that telomerase is a particularly attractive target for the tumor- specific expression system of vectors. We demonstrate here that by using the hTERT promoter-driven caspase-8 expression vector (hTERT/caspase-8), apoptosis is restricted to telomerase-positive tumor cells of wide range, and is not seen in normal fibroblast cells without telomerase activity. Furthermore, treatment of subcutaneous tumors in nude mice with the hTERT/caspase-8 construct inhibited tumor growth significantly because of induction of apoptosis (p &lt
    0.01). The telomerase-specific expression of apoptosis-inducible genes afforded by the hTERT promoter, therefore, may be a novel and promising targeting approach for the treatment of tumors with telomerase activity.

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  • Chromosomal mapping of Adam9, Adam15 and Adam21."jointly worked"

    Matrix Biol.   May;19(2):185-7 ( 2 )   185 - 187   2000年5月

  • ADAM-TS8, a novel metalloprotease of the ADAM-TS family located on mouse chromosome 9 and human chromosome 11."jointly worked"

    Genomics.   Dec 1;62(2):312-5 ( 2 )   312 - 315   1999年12月

  • ADAM-TS5, ADAM-TS6, and ADAM-TS7, novel members of a new family of zinc metalloproteases. General features and genomic distribution of the ADAM-TS family."jointly worked"

    J Biol Chem.   Sep 3;274(36):25555-63 ( 36 )   25555 - 25563   1999年9月

  • Chromosomal assignment of two ADAM genes, TACE (ADAM17) and MLTNB (ADAM19), to human chromosomes 2 and 5, respectively, and of Mltnb to mouse chromosome 11.

    Genomics.   Nov 15;54(1):178-9 ( 1 )   178 - 179   1998年11月

  • Cloning of the human tissue inhibitor of metalloproteinase-4 gene (TIMP4) and localization of the TIMP4 and Timp4 genes to human chromosome 3p25 and mouse chromosome 6, respectively."jointly worked"

    Genomics.   Jul 1;51(1):148-51 ( 1 )   148 - 151   1998年7月

  • Time-dependent alterations of serum levels of triple-helix domain and 7S domain of type IV collagen in patients with acute myocardial infarction after successful reperfusion: Limited relation to left ventricular ejection fraction

    Y Kajikawa, S Kusachi, J Kondo, Sano, I, K Yamamoto, S Hirohata, M Murakami, T Murakami, T Tsuji

    CLINICA CHIMICA ACTA   258 ( 2 )   241 - 247   1997年2月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE BV  

    DOI: 10.1016/S0009-8981(96)06470-4

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  • Time dependent alterations of serum matrix metalloproteinase-1 and metalloproteinase-1 tissue inhibitor after successful reperfusion of acute myocardial infarction

    Satoshi Hirohata, Shozo Kusachi, Masahiro Murakami, Takashi Murakami, Issei Sano, Tomoko Watanabe, Issei Komatsubara, Jun Kondo, Takao Tsuji

    Heart   78 ( 3 )   278 - 284   1997年

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    記述言語:英語   出版者・発行元:BMJ Publishing Group  

    Objective - To test the hypothesis that changes in serum matrix metalloproteinase-1 (MMP-1) and tissue inhibitors of metalloproteinase-1 (TIMP-1) after acute myocardial infarction reflect extracellular matrix remodelling and the infarct healing process. Patients - 13 consecutive patients with their first acute myocardial infarction who underwent successful reperfusion. Methods - Blood was sampled on the day of admission, and on days 2, 3, 4, 5, 7, 14, and 28. Serum MMP-1 and TIMP-1 were measured by one step sandwich enzyme immunoassay. Left ventricular volume indices were determined by left ventriculography performed four weeks after the infarct. Results - Serum concentrations of both MMP-1 and TIMP-1 changed over time. The average serum MMP-1 was more than 1 SD below the mean control values during the initial four days, increased thereafter, reaching a peak concentration around day 14, and then returned to the middle control range. Negative correlations with left ventricular end systolic volume index and positive correlations with left ventricular ejection fraction were obtained for serum MMP-1 on day 5, when it began to rise, and for the magnitude of rise in MMP-1 on day 5 compared to admission. Serum TIMP-1 at admission was more than 1 SD below the mean control value, and increased gradually thereafter, reaching a peak on around day 14. Negative correlations with left ventricular end systolic volume index and positive correlations with left ventricular ejection fraction were obtained for serum TIMP-1 on days 5 and 7, and for the magnitude of rise in TIMP-1 on days 5 and 7 compared to admission. Conclusions -Both MMP-1 and TIMP-1 showed significant time dependent alteration after acute myocardial infarction. Thus MMP-1 and TIMP-1 may provide useful information in evaluating the healing process as it affects left venticular remodelling after acute myocardial infarction.

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  • Laminin alpha 1, alpha 2, alpha 4 and beta 1 chain mRNA expression in mouse embryonic, neonatal, and adult hearts.

    Jpn Heart J.   Mar;38(2):281-9 ( 2 )   281 - 289   1997年

  • Tenascin expression in endomyocardial biopsy specimens in patients with dilated cardiomyopathy: Distribution along margin of fibrotic lesions

    A. Tamura, S. Kusachi, I. Nogami, A. Yamanishi, Y. Kajikawa, S. Hirohata, T. Tsuji

    Heart   75 ( 3 )   291 - 294   1996年

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    記述言語:英語   出版者・発行元:BMJ Publishing Group  

    Objective - To examine the hypothesis that tenascin, an extracellular matrix glycoprotein, contributes to fibrotic changes in dilated cardiomyopathy. Methods - The localisation of tenascin in biopsy specimens of the hearts obtained from eight patients with dilated cardiomyopathy was examined using staining by the avidin-biotin-peroxidase complex method Results - (1) Perimysium and endomysium. Although positive staining for tenascin was observed in the enlarged perimysium and endomysium in all patients, moderately intense staining was characteristically observed near the replacement fibrotic lesions. In the narrow perimysium and endomysium of the myocardium not containing replacement fibrotic lesions, tenascin was not present, as in the control specimens. (2) Replacement fibrotic lesions. Non-homogeneous positive staining for tenascin was detected in all replacement fibrotic lesions examined. Intense tenascin deposition was observed in the peripheral portion of the replacement fibrotic lesions. The tenascin staining observed in the small replacement fibrotic lesions was more intense than that in the large lesions. Conclusions - Tenascin contributes to the development of the fibrotic changes seen in the dilated cardiomyopathic heart. Its characteristic location, specifically the distribution along the margin of the fibrosis, suggests that fibrotic change is a continuous process in hearts with dilated cardiomyopathy.

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  • Reperfusion hastens appearance and extent of distribution of type I collagen in infarct zone: Immunohistochemical study in rat experimental infarction

    S. Yamasaki, S. Kusachi, H. Moritani, J. Kondo, S. Hirohata, A. Tamura, T. Tsuji

    Cardiovascular Research   30 ( 5 )   763 - 768   1995年

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    記述言語:英語  

    Background: The effects of reperfusion on time-dependent alteration of type I collagen have not been examined. Objectives: We compared the sequential changes in the appearance and distribution of type I collagen in reperfused infarct rat hearts to those in non-reperfused hearts. Methods: Using an experimental rat model of infarction, we performed immunohistochemical staining with a polyclonal antibody to type I collagen by the avidin-biotin-peroxidase method. Reperfusion was established after 2-h coronary ligation that produced complete necrosis of myocytes. Results: In reperfused hearts, type I collagen appeared in the peripheral zone of the infarct at day 2, which was 1 day earlier than in non-reperfused hearts. The extent of distribution of type I collagen in reperfused hearts was comparable to that observed approximately 1 day later in non-reperfused hearts. Conclusion: Reperfusion can accelerate collagen matrix formation compared with that in non-reperfused hearts after acute myocardial infarction.

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▼全件表示

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  • The Westerizaton of Life Style and Atherosclerosis in Japan –The Balance of EPA and AA-

    第86回欧州動脈硬化会議  2018年 

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  • Supplementation of Omega-3 PUFAs could improve long term prognosis after PCI in patients without hyperlipidemia and diabetes.

    第86回欧州動脈硬化会議  2018年 

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  • Molecular and biochemical analysis of HYBID (HYaluronan-Binding protein Involved in hyaluronan Depolymerization) gene expression.

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    2017 年度生命科学系学会合同年次大会  2017年 

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    第76回日本循環器学会総会  2012年 

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    第76回日本循環器学会総会  2012年 

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    第76回日本循環器学会総会  2012年 

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  • ヒアルロン酸(HA)分子量と関節軟骨保護効果の解析

    第44回日本結合組織学会学術大会 第59回マトリックス研究会大会 合同学術集会  2012年 

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  • ADAMTS1ノックアウトマウスの解析

    第44回日本結合組織学会学術大会 第59回マトリックス研究会大会 合同学術集会  2012年 

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  • Cyclic tensile strain inhibits Interleukin-1β and Tumor Necrosis Factor-α induced aggrecanase in human chondrosarcoma cell line OUMS-27 by stretch-activated channels

    2012 Biennial Meeting of American Society for Matrix Biology  2012年 

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  • The tumor growth inhibitory effect of ADAMTS1 is accompanied by the inhibition of tumor angiogenesis

    2012 Biennial Meeting of American Society for Matrix Biology  2012年 

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  • リンパ管内皮細胞に対するADAMTS1の作用とシグナル伝達

    第85回日本生化学会大会  2012年 

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  • The inhibitory effect of an angiotensin II converting enzyme inhibitor on gelatinase activity in experimental abdominal aortic aneurysm

    第20回日本血管生物医学会  2012年 

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  • メカニカルストレスとサイトカイン

    第25回日本軟骨代謝学会  2012年 

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  • ADAMTS1 plays a role in apoptosis by mediating TNF-α receptor1

    第76回日本循環器学会総会  2012年 

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  • ADAMTS1プロモーターは急性低酸素応答性に遺伝子を発現する

    第8回がんとハイポキシア研究会  2011年 

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  • ADAMTS1 plays roles in endothelial cell apoptosis

    アメリカ心臓協会(AHA) 学術集会  2011年 

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  • ADAMTS1のin vitroでのリンパ管新生阻害効果

    第84回日本生化学会大会  2011年 

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  • 非糖尿病性未治療高血圧患者におけるUACRの分布とhigh-normalの頻度

    第58回日本臨床検査医学会学術集会  2011年 

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  • 急性冠症候群患者における血清ADAMTS1レベルの上昇

    第58回日本臨床検査医学会学術集会  2011年 

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    第58回日本臨床検査医学会学術集会  2011年 

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  • Hyaluronan inhibits aggrecanase in human chondrosarcoma cell line OUMS-27 in a size dependent manner

    MBJ2011 第34回日本分子生物学会年会  2011年 

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  • 虚血性心疾患患者によるCAVIと冠動脈硬化、左心機能の関連性の検討

    第58回日本臨床検査医学会学術集会  2011年 

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  • Attenuation of endothelial apoptosis induced by TNF-alpha in ADAMTS1 deficient cells

    ゴードンカンファレンス matrix metalloproteinase  2011年 

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  • Hypertension and Aging are the Risk Factors to Lead AMI for Patients with a Favorable AA to EPA Balance

    第75回日本循環器学会総会  2011年 

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  • アンジオテンシンⅡ受容体拮抗薬(オルメサルタン)によるサイトカイン発現抑制効果と心機能保持効果

    第43回日本結合組織学会学術大会・第58回マトリックス研究会大会 合同学術集会  2011年 

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  • ADAMTS1は腫瘍壊死因子刺激下の内皮細胞におけるアポトーシスに関連する

    第43回日本結合組織学会学術大会・第58回マトリックス研究会大会 合同学術集会  2011年 

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  • Endothelial cell-specific early immediate response gene expression in hypoxia

    第43回日本動脈硬化学会学術集会  2011年 

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  • A ratio of MDA-LDL to LDL-C represents plaque vulnerability in a patient with angina pectoris: VH-IVUS study

    第43回日本動脈硬化学会学術集会  2011年 

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  • Plasma Adipocyte Fatty Acid-binding Protein is Associated with Chronic Kidney Disease and Coronary Lesion Severity in Type2 Diabetic Patients

    第75回日本循環器学会総会  2011年 

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  • The role of alpha556 chains of type IV collagen in restenosis after angioplasty

    第43回日本動脈硬化学会学術集会  2011年 

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  • Impact of CD44 on the Development of Abdominal Aortic Aneurysm in Mice: the Interaction with Hyaluronic Acid and Macrophages

    第75回日本循環器学会総会  2011年 

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  • Olmesartan Reduces Serum Adipocyte Fatty Acid-Binding Protein and Arterial Stiffness in Hypertensive Patients

    第75回日本循環器学会総会  2011年 

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  • ADAMTS1 is a novel acute biphasic marker for ischemia and reperfusion in myocardial infarction

    欧州心臓学会議(ESC)  2011年 

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  • Altered Expression of Hypoxia Response in Ischemic Hind Limb in ADAMTS1 Hetero Mice

    第5回高度医療都市を創出する未来技術国際シンポジウム  2011年 

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  • ヒアルロン酸分子量とアグリカナーゼ発現抑制効果に関する検討

    第24回日本軟骨代謝学会  2011年 

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  • ADAMTS1は血管新生を阻害しアポトーシスを誘導する

    第43回日本結合組織学会学術大会・第58回マトリックス研究会大会 合同学術集会  2011年 

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  • ADAMTS1 inhibit angiogenesis by inducing apoptosis in endothelial cells: in vitro and in vivo study

    第4回高度医療都市を創出する未来技術国際シンポジウム  2011年 

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  • ADAMTS1 induces apoptosis on endothelial cells

    第9回トルコ遺伝子医学会学術集会  2010年 

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  • ADAMTS1の内皮細胞に対するアポトーシス効果の検討

    第42回日本結合組織学会学術大会・第57回マトリックス研究会大会 合同学術集会  2010年 

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  • Cd44 Contributes to the Development of Abdominal Aortic Aneurysm in Mice Through the Interaction With Hyaluronic Acid and the Recruitment of Macrophages

    アメリカ心臓協会(AHA) 学術集会  2010年 

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  • ADAMTS1のin vitroでのリンパ管新生阻害効果

    第42回日本結合組織学会学術大会・第57回マトリックス研究会大会 合同学術集会  2010年 

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  • Estimated GFR and omega 6 to 3 PUFAs balance (AA/EPA) has no significant relationship to ox-LDL level in patients with coronary heart disease.

    第42回 日本動脈硬化学会・学術集会  2010年 

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  • Ox-LDL (MDA-LDL) is strongly influenced by LDL/HDL-C ratio, and significantly higher in patients with ACS than SAP or normal coronary.

    第42回 日本動脈硬化学会・学術集会  2010年 

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  • ADAMTS1遺伝子治療はプロテアーゼ非依存的に血管新生阻害効果を発揮し、腫瘍増大を阻害する

    第42回日本結合組織学会学術大会・第57回マトリックス研究会大会 合同学術集会  2010年 

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  • プロテアーゼ活性に依存しない血管内皮細胞への作用によりADAMTS1は腫瘍発育を阻害する

    第7回日本病理学会カンファレンス  2010年 

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  • アンジオテンシンⅡ受容体拮抗薬(オルメサルタン)による新負荷モデルラットのCTGF発現抑制効果

    第42回日本結合組織学会学術大会・第57回マトリックス研究会大会 合同学術集会  2010年 

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  • 心筋芽細胞分化促進因子の心筋梗塞および活性酸素細胞障害に対する効果

    第42回日本結合組織学会学術大会・第57回マトリックス研究会大会 合同学術集会  2010年 

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  • Distribution of Plaque-Targeting Fluorescent Accumulation were associated with condensed Vascular Formation from the Vasa Vasorum in Atherosclerotic Plaque

    第73回日本循環器学会総会  2010年 

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  • A Novel Cationic Protein Protected H9c2 Cells from Oxidative Stress Induced by H2O2 through Akt Signaling

    第73回日本循環器学会総会  2010年 

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  • Sexual Difference of Risk Factors Related to Plaque Vulnerability: A Study with VH-IVUS

    第73回日本循環器学会総会  2010年 

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  • Increased Plasma Adipocyte Fatty Acid-binding Protein as a Risk of Coronary Artery Disease in Men

    第73回日本循環器学会総会  2010年 

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  • 好酸球カチオンタンパク質はH2O2刺激下H9C2細胞に保護的に働く

    第51回日本生化学会 中国四国支部例会  2010年 

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  • The role of CD44 in the Development of Experimental Abdominal Aortic Aneurysm

    第73回日本循環器学会総会  2010年 

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  • ADAMTS1 is a Novel Biomarker for Acute ischemia/reperfusion in Myocardial infarction Patients

    第73回日本循環器学会総会  2010年 

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  • Serum Adipocyte Fatty Acid-Binding Protein is Associated With Coronary Lesion Complexity in Patients With Coronary Artery Disease

    アメリカ心臓協会(AHA) 学術集会  2010年 

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  • ADAMTS1 gene transfer inhibits angiogenesis and tumor growth

    第9回トルコ遺伝子医学会学術集会  2010年 

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  • Chronic Kidney Disease is a Strong Predictor Related to the Severity of Coronary Artery Lesion in Patients with Stable Angina Pectoris

    アメリカ心臓協会(AHA) 学術集会  2010年 

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  • 新規急性低酸素応答配列を用いた遺伝子発現ベクターによる急性低酸素下のレポーター遺伝子の発現様式

    第33回日本分子生物学会年会 第83回日本生化学会大会合同大会  2010年 

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  • ADAMTS1プロモーターは急性低酸素状態の内皮細胞選択的に遺伝子発現を誘導する

    第42回日本結合組織学会学術大会・第57回マトリックス研究会大会 合同学術集会  2010年 

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  • HIF-1 Directly Induced Novel Metalloproteinase ADAMTS1 Expression and ADAMTS1 under Hypoxia Accelerated Endothelial Cell Migration

    第73回日本循環器学会総会  2009年 

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  • Association of Increased Plasma Adipocyte Fatty Acid-binding Protein With Coronary Artery Disease in Men.

    アメリカ心臓協会(AHA) 学術集会  2009年 

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  • ADAMTS-1 is an Endothelial Cell-specific Hypoxia-inducible Gene.

    アメリカ心臓協会(AHA) 学術集会  2009年 

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  • A Novel Cationic Protein Reduced Infracted Size and Protected Myocytes From Oxidative Stress Through Modification of Akt Signaling.

    アメリカ心臓協会(AHA) 学術集会  2009年 

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  • Average age of acute myocardial infarction (AMI) began to decline due to increase of younger age AMI in our hospital.

    第41回日本動脈硬化学会総会  2009年 

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  • The ratio of n-6 to n-3 polysaturated fatty acids reflects vulnerability of coronary plaques: a study with a virtual histology intravascular ultrasound.

    第41回日本動脈硬化学会総会  2009年 

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  • Atrial stiffness is an independent determinant of B-type natriuretic peptide in patients with paroxysmal atrial fibrillation

    欧州心臓協会(ESC)年次集会  2009年 

     詳細を見る

  • The association of serum adipocyte fatty acid binding protein with coronary atherosclerotic burden measured by intravascular ultrasound

    欧州心臓協会(ESC)年次集会  2009年 

     詳細を見る

  • HIF-1 directly induced ADAMTS1 mRNA expression in hypoxic endothelial cells.

    MMPゴードンカンファレンス  2009年 

     詳細を見る

  • Combination therapy of angiontensin II receptor blockers plus a calcium channel blocker, but not a diuretic, improve late systolic pressure augmentation index in elderly patients with essential hypertension

    欧州心臓協会(ESC)年次集会  2009年 

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  • Beneficial effect of combination treatment with angiotensin II receptor blockers plus a calcium channel blocker on augmentation index in elderly patients with essential hypertension

    第19回 欧州高血圧会議  2009年 

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  • Gene transfer of ADAMTS1 induced apoptosis in endothelial cells and inhibited tumor growth

    PPCTSS (PanPacific Connective Tissue Society Symposium)  2009年 

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  • Angiosculpt is a unique and powerful ballooning device to score a highly calcified lesion and in-stent restenosis.

    第18回日本心血管インターベンション治療学会 CVIT2009学術集会  2009年 

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  • The effect of olmesartan, an angiotensin II receptor blocker on the relationship between adiponectin and arterial stiffness in hypertensive patients with high body mass index

    第19回 欧州高血圧会議  2009年 

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  • Utilization of ADAMTS1 as A New Tool For Detecting Hypoxia

    第3回 国際分子医学集会  2009年 

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  • In vivo imaging of Atherosclerosis with Targeting Liposome and its availability as a Drug Delivery System

    第10回 国際細胞移植学会  2009年 

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  • Identification of NF-κB binding elements in human ADAMTS9 promoter

    第3回 国際分子医学集会  2009年 

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  • The 3’-untranslated Region of ADAMTS1 Regulates Its Expression

    第3回 国際分子医学集会  2009年 

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  • ADAMTS1 as a hypoxia sensing biomarker

    PPCTSS (PanPacific Connective Tissue Society Symposium)  2009年 

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  • ADAMTS1 is induced by hypoxia in endothelial cells and HIF-1 binds to the ADAMTS1 promoter

    PPCTSS (PanPacific Connective Tissue Society Symposium)  2009年 

     詳細を見る

  • Eosinophil Cationic Protein (ECP) Protects hearts against myocardial infarction

    PPCTSS (PanPacific Connective Tissue Society Symposium)  2009年 

     詳細を見る

  • Olmesartan Decreased Serum TGF-β Level and Protected Fibrotic Change in Rat Pressure Overload Heart

    第73回日本循環器学会総会  2009年 

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  • Difference of Risk Factors and PUFAs between Generations and Sex in Patients of Acute Myocardinal Infarction

    第73回日本循環器学会総会  2009年 

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  • Heart Rate Circadian Rhythm is the Strongest Factor to Determine the BNP Level in Permanent AF without LV Systolic Dysfunction

    第73回日本循環器学会総会  2009年 

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  • Differential Effects of Calcium Channel Blocker and Diuretic in Combination with Angiotensin II Receptor Blockers on Late Systolic Pressure Augmentation

    第73回日本循環器学会総会  2009年 

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  • A Novel Drug Delivery System with Targeting Liposome Reduced Inflammation in Macrophages

    第73回日本循環器学会総会  2009年 

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  • Significant Increase of Cholesterol, Trigriceride and AA were Observed in AMI; From 20 Years Database in Mitoyo General Hospital

    第73回日本循環器学会総会  2009年 

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  • Relationship between Adipocyte Fatty Acid-Binding Protein and Coronary Plaque Burden - An Intravascular Ultrasound Study.

    第73回日本循環器学会総会  2009年 

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  • QT Prolongation and Global ST-T Change are the Characteristics of Electrocardiogram of Heat Stroke

    第73回日本循環器学会総会  2009年 

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  • OUMS-27軟骨肉腫細胞または軟骨細胞におけるNFATc1を解したIL-1bによるADAMTS9遺伝子の活性化

    第22回日本軟骨代謝学会  2009年 

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  • 低分子ヒアルロン酸によるサイトカイン誘導とヒアルロン酸レセプター

    第22回日本軟骨代謝学会  2009年 

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  • Two Hyaluronan Receptors, Toll-like receptor-4 (TLR4) and CD44, Play Distinct Roles in Cytokine Induction in Monocytes

    第73回日本循環器学会総会  2009年 

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  • 発作性心房細動患者におけるBNP上昇と橈骨動脈AIとの増加の関係

    第40回日本動脈硬化学会総会  2008年 

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  • 高血圧患者における発作性心房細動とAugmentation Indexの増加との関係

    第31回日本高血圧学会総会  2008年 

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  • Association between serum adipocyte fatty acid-binding protein and the extent of coronary atherosclerosis

    第6回アジア動脈硬化学会  2008年 

     詳細を見る

  • Serum Adipocyte Fatty Acid-Binding Protein Levels are Independently Associated with Coronary Atherosclerosis

    アメリカ心臓協会(AHA) 学術集会  2008年 

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  • 高血圧患者へのオルメサルタン投与によるアディポサイトカインへの影響

    第31回日本高血圧学会総会  2008年 

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  • CAVIは左室拡張障害の指標となるか?

    第5回血管バイオメカニクス研究会  2008年 

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  • The Impact of Increased Augmentation Index of Radial Pressure Waveform on Paroxysmal Atrial Fibrillation

    アメリカ心臓協会(AHA) 学術集会  2008年 

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  • The Inhibiton of the ADAMTS9 induced by Interleukin 1β using 11R-VIVIT peptide in OUMS-27 Chondrosarcoma Cells and in Human Chondrocytes

    アメリカマトリックス研究会学術集会  2008年 

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  • siRNA silencing reveals the role of vascular cell adhesion molecule-1 in vascular smooth muscle cell migration

    第72回日本循環器学会総会  2008年 

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  • Unique Three-dimensional Construction of Neovessel Formation by Fluvastatin Treatment in the Infarcted Myocardium.

    第72回日本循環器学会総会  2008年 

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  • Activin A as a Novel Marker of Infarct Size in Patients with Acute Myocardial Infarction Who Undergo Percutaneous Coronary Intervention

    第72回日本循環器学会総会  2008年 

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  • Cardiac Myoblast Differentiation Promoting Factor Reduced Infarct Size and Preserved Cardiac Function in Rat Myocardial Infarction Model.

    第72回日本循環器学会総会  2008年 

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  • Increased augmentation index of radial pulse wave in patients with paroxysmal atrial fibrillation

    アメリカ心臓学会(ACC) 学術集会  2008年 

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  • In vivo Imaging of Atherosclerosis with Novel Targeting Liposomes

    第72回日本循環器学会総会  2008年 

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  • 冠動脈疾患患者におけるCardio-ankle vascular index (CAVI)と腎機能低下の関連

    第40回日本動脈硬化学会総会  2008年 

     詳細を見る

  • ADAMTS/aggrecanases are differentially regulated following spinal cord injury

    MMPゴードンカンファレンス  2007年 

     詳細を見る

  • Expression of ADAMTS9 gene in chondrocytes and its regulation

    第20回日本軟骨代謝学会  2007年 

     詳細を見る

  • Tolerance and Diagnostic Accuracy of Adenosine Infusion for Myocardial Perfusion SPECT in a Japanese Population

    第71回日本循環器学会総会  2007年 

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  • ADAMTS1 Inhibits Angiogenesis via Metalloprotease-independent Endothelium-specific Activity

    第71回日本循環器学会総会  2007年 

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  • Serum Activin A Level Is Associated With Infarct Size In Patients With Acute Myocardial Infarction Who Undergo Successful Primary Percutaneous Coronary Intervention

    アメリカ心臓協会 学術集会  2007年 

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  • 非侵襲的な動脈硬化指標CAVI(Cardio-ankle vascular index)は心臓超音波 検査における左室拡張能の指標と関連するか?

    第39回日本動脈硬化学会総会  2007年 

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  • Complexity of differential response to hyaluronan stimulation of hyaluronan-receptors in human peripheral blood mononuclear cells

    第30回日本分子生物学会年会・第80回日本生化学会大会 合同大会  2007年 

     詳細を見る

  • Frequency of Early Repolarization in Electrocardiogram in Chronic Hemodialys is Patients and its Clinical Characteristics

    第71回日本循環器学会総会  2007年 

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  • Olmesartan Attenuated Connective Tissue Growth Factor (CTGF) Expression in Vascular Smooth Muscle Cells and Ameliorated Cardiac Hypertrophy in Pressure-overload Rats

    第71回日本循環器学会総会  2007年 

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  • CELLULAR MECHANISM FOR CYTOKINE INDUCTIONS IN HYALURONAN-STIMULATED HUMAN MONONUCLEAR CELLS

    ヒアルロン酸サミッ  2007年 

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  • Differential LDL-oxidation by endothelial cells in mouse strains with different atherosclerosis susceptibility

    第71回日本循環器学会総会  2007年 

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  • ADAMTS-aggrecanases are differentially expressed in cultured astrocyte

    第39回日本結合組織学会学術大会・第54回マトリックス研究会大会 合同学術集会  2007年 

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  • Endothelium-specific inhibition of cell migration and proliferation by ADAMTS1

    第39回日本結合組織学会学術大会・第54回マトリックス研究会大会 合同学術集会  2007年 

     詳細を見る

  • ADAMTS1 is hypoxia inducible gene in endothelial cells

    MMPゴードンカンファレンス  2007年 

     詳細を見る

  • Differential Expression of ADAMTS1 gene in cancer cell lines

    第39回日本結合組織学会学術大会・第54回マトリックス研究会大会 合同学術集会  2007年 

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  • Versicanolysis was accelerated in the border zone of myocardial infarction

    MMPゴードンカンファレンス  2007年 

     詳細を見る

  • ピタバスタチンの脂質低下作用と動脈効果改善作用―多施設臨床試験による検討

    第39回日本動脈硬化学会総会  2007年 

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  • Adenoviral gene therapy using NC1 domain of collagen IV suppresses vessel formation and tumor growth

    欧州結合組織連合学術集会(FECTS)  2006年 

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  • ヒト末梢血単球成分におけるヒアルロン酸の炎症反応誘導機構の解析

    第37回日本動脈硬化学会総会  2006年 

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  • Expression Profile of ADAMTS-aggrecanases in Head and Neck Squamous Cell Carcinomas

    欧州結合組織連合学術集会(FECTS)  2006年 

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  • Statin treatment accelerated neovessel formation in the border zone of the infarcted heart: Architectural study by vascular corrosion casting method using scanning electron microscopy.

    アメリカ心臓病協会(AHA)年次集会  2006年 

     詳細を見る

  • Tolerance and diagnostic accuracy of an adenosine infusion for myocardial scintigraphy in Japanese

    ヨーロッパ核医学協会2006年次集会  2006年 

     詳細を見る

  • 動脈硬化感受性の異なるマウス系統間における血管平滑筋の酸化LDLに対する反応

    第89回日本循環器学会中国地方会  2006年 

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  • Decreased serum levels of interferon gamma inducible protein 10 (IP-10) in acute myocardial infarction patients after successful primary percutaneous coronary intervention are associated with a smaller infarct size

    アメリカ心臓病協会(AHA)年次集会  2006年 

     詳細を見る

  • 内皮細胞特異的に作用するADAMTSプロテアーゼ由来新規ドメインの機能解析

    日本分子生物学会 2006 フォーラム  2006年 

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  • ADAMTSプロテアーゼのうちADAMTS-4が心筋梗塞早期に誘導され、梗塞辺縁部でバーシカンを分解する

    日本分子生物学会 2006 フォーラム  2006年 

     詳細を見る

  • Aggrecanase member of ADAMTS proteases are differently regulated in ventricular remodeling

    第20回国際生化学・分子生物学会議 (IUBMB)  2006年 

     詳細を見る

  • Hyaluronan induced cytokine expression in peripheral blood mononuclear cells

    グライコマトリックス国際シンポジウム(Extracellular Glycomatrix in Health and Disease Symposium)  2006年 

     詳細を見る

  • Architectural Change in the Neovessels in Infarct Border Zone after Myocardial Infarction by Scanning Electron Microscopy: Impact of Statin Treatment

    第70回日本循環器学会学術集会  2006年 

     詳細を見る

  • Cytokine-induced ADAMTS9 expression is inhibited by NF kappa beta inhibitors in chondrocytic cells

    第53回マトリックス研究会大会  2006年 

     詳細を見る

  • Changes in Serum Interferon-gamma Inducible Protein 10(IP-10) Levels Correlated with Ventricular Function and Infarct Size in Acute Myocardial Infarction Patients

    第70回日本循環器学会学術集会  2006年 

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  • 待機的PCI施行中に左冠動脈主幹部閉塞を呈した一例

    第88回日本循環器学会中国四国合同地方会  2006年 

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  • Tumor-specific expression of the noncollagenous domain-1 of collagen IV suppresses endothelial tube formation and tumor growth in mice

    第38回日本結合組織学会学術大会  2006年 

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  • 留置後9ヶ月で血栓性閉塞をきたしたcovered stentの一症例

    第88回日本循環器学会中国四国合同地方会  2006年 

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  • 無痛性甲状腺炎にて急性増悪したと考えられる拡張型心筋症の一例

    第88回日本循環器学会中国四国合同地方会  2006年 

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  • Evidence for the Proteolytic Cleavage of Versican in Infarct Heart

    第69回日本循環器学会総会  2005年 

     詳細を見る

  • バーシカンはラット心筋梗塞において一時的に上昇し、その発現は再潅流障害により増強する

    第37回日本動脈硬化学会総会  2005年 

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  • GM-CSF刺激により、ヒト末梢血単核球におけるバーシカンの発現は増加する

    第37回日本結合組織学会学術大会  2005年 

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  • Increase in Connective Tissue Growth Factor (CTGF) Expression Precedes Extrracellular Matrix (ECM) Gene Expressions in Pressure-overload Heart in Rats

    第69回日本循環器学会総会  2005年 

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  • HyaluronanはCD44を介しcytokine分泌と共に細胞外matrix発現促進に働く:炎症時に単球で働くmatricrine機構

    第86回日本循環器学会中国地方会  2005年 

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  • ADAMTS9 is synergistically induced by IL-1 and TNF- in OUMS-27 chondrosarcoma cells and in human chondrocytes.

    第18回日本軟骨代謝学会  2005年 

     詳細を見る

  • Lp3/Hapln3 Expression is Coordinately Upregulated with Versican in Balloon-injured Artery and is Enhanced by PDGF in Arterial Smooth Muscle Cell.

    第69回日本循環器学会総会  2005年 

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  • IL-1 and TNF- Induced expression of ADAMTS9 in chondrosarcoma cells is inhibited by MAPK inhibitors, SB203580 and PD98059.

    第52回マトリックス研究会大会  2005年 

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  • Matricellular Protein Thrombospondin-1 (TSP-1) Enhances the Release of Inflammatory Cytokine Interleukin-6 in LPS and PMA-stimulated Human Peripheral Blood Mononuclear Cells

    第69回日本循環器学会総会  2005年 

     詳細を見る

  • Aggrecanases are differently regulated by IL-1b and TNF-a in chondrosarcoma cell line.

    欧州結合組織連合学術集会(FECTS)  2004年 

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  • Newly formed relatively large vessels after myocardial infarction express matricellular protein, Thrombospomndin-1 (TSP-1) in rats: Comparison with real-time RT-PCR analysis

    第68回日本循環器学会総会  2004年 

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  • Low dose of Cerivastatin increased microvessel formation and induced angiogenesis in conjunction with attenuating anti-angiogenic protein in rat myocardial infarction

    第68回日本循環器学会総会  2004年 

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  • Increments of serum chemokine interferon-gamma inducible protein 10 (IP-10) levels correlated with left ventricular function in acute myocardial infarction patients

    第68回日本循環器学会総会  2004年 

     詳細を見る

  • Dynamic Induction of ADAMTS1 Gene in the Early Phase of Acute Myocardial Infarction

    Second National Meeting of the American Society for Matrix Biology  2004年 

     詳細を見る

  • Lp3/Hapln3, a novel link protein which colocalizes with versican and is coordinately upregulated by PDGF.

    Second National Meeting of the American Society for Matrix Biology  2004年 

     詳細を見る

  • 血管傷害モデルにおけるヒアルロン酸結合リンクプロテインLp3/Hapln3の発現解析

    第77回日本生化学会大会  2004年 

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  • 軟骨細胞におけるIL-1βとTNF-αによるアグリカナーゼ遺伝子発現誘導の多様性

    第77回日本生化学会大会  2004年 

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  • Hapln3 Is a Novel Extracellular Matrix Protein Limited To Vessels and Is Upregulated in Pressure Overload Heart

    アメリカ心臓病協会(AHA)年次集会  2004年 

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  • Endothelial Cells of Newly Formed Vessels Express Connective Tissue Growth Factor (CTGF), Osteonectin and Osteopontin mRNAs in the Border Zone of Myocardial Infarction in Rats

    アメリカ心臓病協会(AHA)年次集会  2004年 

     詳細を見る

  • ADAMTS-1, A Disintegrin And Metalloprotease with ThromboSpondin motifs-1, Is a Novel Hypoxic Immediate Gene Expressed by Endothelial Cells

    第68回日本循環器学会総会  2004年 

     詳細を見る

  • Serum Antibodies to Human Heat Shock Protein 60 Is Elevated in Subjects With Unstable Angina Pectoris

    第68回日本循環器学会総会  2004年 

     詳細を見る

  • Identification and Characterization of a novel rat link protein: Lp3/Hapln3

    第83回日本循環器学会中国地方会  2004年 

     詳細を見る

  • Vasl1 (Vascular Link Protein-1) Is a Novel Extracellular Matrix Protein Limited To Vessels and Is Upregulated in Pressure Overload Heart

    第68回日本循環器学会総会  2004年 

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  • 新規マトリックスリンクプロテインLp3/Hapln3: クローニングおよびその発現解析

    第36回日本動脈硬化学会総会  2004年 

     詳細を見る

  • Metalloprotease ADAMTS-1 Was Rapidly Expressed by Endothalial Cells in Acute Myocardial Infarction and Its Quantitative Analysis by Real-Time PCR

    第67回日本循環器学会総会  2003年 

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  • Late Reperfusion Enhanced Gelatinolysis in Infarct Periphreral Zone: Analysis by in Situ Zymogram Analysis in Rats

    第67回日本循環器学会総会  2003年 

     詳細を見る

  • Differential expression of ADAM-TS family members in osteosarcoma cell line (OUMS-27)

    第44回日本生化学会 中国四国支部例会  2003年 

     詳細を見る

  • Endothelial Cells of Newly Formed Vessels in the Border Zone of Myocardial Infarction Express Proteoglycan Decorin and Biglycan

    第67回日本循環器学会総会  2003年 

     詳細を見る

  • Expression of Versican and its Degrading Enzymes in Acute Myocardial Infarction

    5th Pan-Pacific Connective Tissue Societies Symposium (PCTSS)  2003年 

     詳細を見る

  • スタチンによる心筋梗塞後の血管新生誘導は血管新生阻害因子制御を介している

    第82回日本循環器学会中国地方会  2003年 

     詳細を見る

  • Identification of the novel rat Vascular link protein, Vasl1

    第76回日本生化学会大会  2003年 

     詳細を見る

  • ADAMTS-1, A disintegrin and metalloprotease with thrombospondin motifs-1, is a novel hypoxic immediate gene expressed by endothelial cells.

    アメリカ心臓病協会(AHA)年次集会  2003年 

     詳細を見る

  • Rapid increase of matrix adhesive glyocprotein, thrombospondin-1 (TSP-1) mRNA in rat myocardial infarction (MI) and its localization

    第66回日本循環器学会総会  2002年 

     詳細を見る

  • Chemokine Receptor CXCR-3 Was Up-regulated in Rat Myocardial Infarction(MI): Anasysis of cDNA Array and Quantitative Expression by Real Time PCR

    第66回日本循環器学会総会  2002年 

     詳細を見る

  • Tissue Inhibitor of Metalloproteinase-2 Localization in Myocardial Infarction (MI) in Rats: Another Role as an Activator for Metalloproteinase-2

    第66回日本循環器学会総会  2002年 

     詳細を見る

  • LAMININ-10: migration promoting activity on vascular endothelial cell

    第80回日本循環器学会中国地方会  2002年 

     詳細を見る

  • Endothelial Cells of Newly Formed Vessels Express Osteonectin mRNAs in the Border Zone of Myocardial Infarction (MI) in Rats

    第66回日本循環器学会総会  2002年 

     詳細を見る

  • 胆嚢炎に続発した感染性腹部大動脈瘤の一例

    第81回日本循環器学会中国四国合同地方会  2002年 

     詳細を見る

  • Heparin Binding Epidermal Growth Factor-like Growth Factor(HB-EGF) is Increased in Myocardial Infarction(MI): Enhancement by Reperfusion and Auto-induction by Recombinant Protein.

    第66回日本循環器学会総会  2002年 

     詳細を見る

  • ラット実験的心筋梗塞モデルにおける新規メタロプロテアーゼADAMTS-1発現様式の検討

    49回 マトリックス研究会大会・日本結合組織学会学術大会  2002年 

     詳細を見る

  • Nicorandil decreased infarct size with enhancement of Serum interleukin 6 levels in patients with acute myocardial infarction after successful reperfusion

    第66回日本循環器学会総会  2002年 

     詳細を見る

  • ADAMTSファミリー ーその多様性―

    第48回マトリックス研究会大会 国際シンポジウム  2001年 

     詳細を見る

  • Rapid and transient up-regulation of ADAMTS-1 (A disintegrin and metalloprotease with thrombospondin motifs) mRNA in rat myocardial infarction.

    第65回日本循環器学会総会・学術集会  2001年 

     詳細を見る

  • Spatial changes of gelatinolytic activity in myocardial infarction in rats: association with expression of matrix metalloproteinase (mmp)-2 and membrane type(mt)1-mmp in the late infarct healing satge

    欧州心臓協会(ESC)年次集会  2001年 

     詳細を見る

  • Spatial changes of gelatinase activities and membrane type 1-matrix metalloproteinase (MT1-MMP) mRNA expression in myocardial infarction of rats

    第65回日本循環器学会総会  2001年 

     詳細を見る

  • Endothelial cells of newly formed vessels express connective tissue growth factor (CTGF) and osteopontin mRNAs in rat myocardial infarction.

    第65回日本循環器学会総会  2001年 

     詳細を見る

▼全件表示

産業財産権

  • がんの非ヒトモデル動物及びその作製方法、がん幹細胞及びその製造方法

    妹尾 昌治, 笠井 智成, 岩▲崎▼ 良章, 大原 利章, 廣畑 聡, 加来田 博貴

     詳細を見る

    出願人:国立大学法人 岡山大学

    出願番号:特願2016-546537  出願日:2016年3月30日

    公開番号:特開2017-086091  公開日:2017年5月25日

    公表番号:WO2016-170938  公表日:2016年10月27日

    特許番号/登録番号:特許第6161828号  登録日:2017年6月23日 

    J-GLOBAL

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  • 再灌流療法の治療効果を判定する方法

    廣畑 聡, 臼井 真一, 草地 省藏

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    出願人:国立大学法人 岡山大学

    出願番号:JP2009069224  出願日:2009年11月11日

    公表番号:WO2010-055867  公表日:2010年5月20日

    PCT/JP2009/069224

    J-GLOBAL

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  • 再灌流療法の治療効果を判定するキット

    廣畑 聡, 臼井 真一, 草地 省藏

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    出願人:国立大学法人 岡山大学

    出願番号:特願2010-537793  出願日:2009年11月11日

    特許番号/登録番号:特許第5651890号  登録日:2014年11月28日 

    J-GLOBAL

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  • 新規DNA断片およびその用途

    廣畑 聡, 二宮 善文, 草地 省藏, オメル、ファルク ハティポール

     詳細を見る

    出願人:国立大学法人 岡山大学

    出願番号:特願2009-552497  出願日:2009年2月4日

    公表番号:WO2009-099112  公表日:2009年8月13日

    特許番号/登録番号:特許第5493231号  登録日:2014年3月14日 

    PCT/JP2009/ 051907

    J-GLOBAL

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  • ECPを有効成分とする左室リモデリングの予防及び治療剤。

    妹尾 昌治, 多田 宏子, 福田 隆之, 廣畑 聡, 丸山 昌彦, 草地 省蔵, 二宮 善文, 五十嵐 貢一

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    出願人:国立大学法人 岡山大学

    出願番号:特願2008-215187  出願日:2008年8月25日

    公開番号:特開2009-073822  公開日:2009年4月9日

    特許番号/登録番号:特許第5467742号  登録日:2014年2月7日 

    J-GLOBAL

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  • 動脈硬化の診断及び治療

    廣畑 聡, 幡中 邦彦, 小川 弘子, 草地 省蔵, 二宮 善文, 五十嵐 貢一

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    出願人:片山化学工業株式会社

    出願番号:特願2007-296159  出願日:2007年11月14日

    公開番号:特開2011-020923  公開日:2011年2月3日

    PCT/JP2008/070817

    J-GLOBAL

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  • 急性虚血性疾患の診断薬

    廣畑 聡, 臼井 真一, 草地 省蔵

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    出願人:国立大学法人 岡山大学

    出願番号:特願2007-230190  出願日:2007年9月5日

    公開番号:特開2009-063353  公開日:2009年3月26日

    特許番号/登録番号:特許第4195492号  登録日:2008年10月3日 

    特許第4195492号

    J-GLOBAL

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  • 物理現象解析支援方法、物理現象解析支援システム、物理現象解析支援プログラム

    中吉 英夫, 廣畑 賢治, 久野 勝美, 青木 秀夫

     詳細を見る

    出願人:株式会社東芝

    出願番号:特願2005-304138  出願日:2005年10月19日

    公開番号:特開2007-114930  公開日:2007年5月10日

    J-GLOBAL

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  • 半導体装置設計支援方法、半導体装置設計支援システム、半導体装置設計支援プログラム

    中吉 英夫, 廣畑 賢治, 青木 秀夫

     詳細を見る

    出願人:株式会社東芝

    出願番号:特願2005-296336  出願日:2005年10月11日

    公開番号:特開2007-108843  公開日:2007年4月26日

    J-GLOBAL

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  • がん細胞特異的遺伝子発現法を用いた血管新生阻害薬

    廣畑 聡, 三好 亨, 土井 正行, 小川 弘子, 二宮 善文

     詳細を見る

    出願人:国立大学法人 岡山大学

    出願番号:特願2005-251732  出願日:2005年8月31日

    公開番号:特開2007-063190  公開日:2007年3月15日

    特許番号/登録番号:特許第4843767号  登録日:2011年10月21日 

    特許第4843767号

    J-GLOBAL

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▼全件表示

受賞

  • Best poster presentation award

    2018年  

     詳細を見る

  • Best poster presentation award

    2018年  

     詳細を見る

  • 優秀演題賞

    2007年  

     詳細を見る

    受賞国:日本国

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共同研究・競争的資金等の研究

  • IL-33を標的とした 改善候補薬による恒常性維持効果の基礎的検討

    研究課題/領域番号:21K06588  2021年04月 - 2024年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    ハティポール オメル・ファルク, 西中 崇, 高橋 英夫, 和氣 秀徳, 西田 圭一郎, 廣畑 聡

      詳細を見る

    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

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  • 細胞との対話を読み解く~エクソソームハンドリングによる変形性関節症の新治療開発

    研究課題/領域番号:20H00548  2020年04月 - 2025年03月

    日本学術振興会  科学研究費助成事業 基盤研究(A)  基盤研究(A)

    廣畑 聡, 岡田 保典, 落谷 孝広, 冨田 秀太, 渡辺 彰吾, 西田 圭一郎, 大月 孝志

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    配分額:45500000円 ( 直接経費:35000000円 、 間接経費:10500000円 )

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  • CCR2陽性マクロファージがNASHの肝線維化を進展させる分子メカニズムの解明

    研究課題/領域番号:19K11791  2019年04月 - 2022年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    稲垣 純子, 渡辺 彰吾, 廣畑 聡

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    非アルコール性脂肪肝炎 (NASH) は、肝硬変・肝がんといった重篤な疾患へと進展する難治性疾患で、肝線維化進展等の病態メカニズムの解明と治療法の開発が急がれている。そこで本研究では、組織マクロファージであるKupffer細胞や肝星細胞などの活性化・分化誘導、骨髄からの炎症性CCR2陽性マクロファージの肝臓への誘引・浸潤・蓄積について、特に、CCR2陽性細胞と、サイトカインとして肝壊死・線維化に重要な役割を有しているとされる細胞外マトリックスタンパク質のオステオポンチンに注目して、肝線維化の分子制御機構を明らかにすることを目的とした。
    SHRSP5/Dmcrラットは、高脂肪高コレステロール (HFC) 食を投与することで顕著なNASH病態に加え炎症細胞の著明な浸潤などの特徴を持つ。このNASHモデル肝組織を用い、まず、CCR2やオステオポンチンの発現・局在を免疫組織染色法にて検討した。その結果、本NASHモデル肝組織において普通食ラットに比べ、CCR2およびオステオポンチン発現の顕著な亢進が認められた。さらに、CCR2とオステオポンチンの局在はほぼ一致し、その部位は、Masson Trichrome 染色により青く染まる膠原線維(コラーゲン線維)部分であることも分かった。また、これらの領域は肝細胞壊死が起きている部位に最も近接した線維化領域であることも確認された。肝線維化においてCCR2陽性細胞とオステオポンチンの関与が示唆された。

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  • メカニカルストレスがもたらすエクソソームの変化:軟骨保護作用の可能性

    研究課題/領域番号:19K09627  2019年04月 - 2021年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    大月 孝志, 古松 毅之, 西田 圭一郎, 廣畑 聡

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    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

    ヒアルロン酸を高濃度で含有する関節液をヒアルロン分解酵素で処理することで再現性良く、高精度で回収できるように既知の方法を改良した。回収された物質が粒子径分布、マーカータンパク確認(western分析)、RNA含量測定等で細胞外であることを確認した。
    我々は変形性関節症(OA)患者の関節液中で上昇し、軟骨マトリックスを分解するマトリックス分解酵素の発現を誘導する炎症性サイトカイン(Interleukin-1β(IL-1β))が軟骨細胞の産生するエクソソームでのCD9(テトラスパニン29)発現を増加していることをwestern分析により明らかにした。患者滑液由来エクソソームにおいてもCD9の発現を確認している。このCD9は細胞接着とシグナル伝達を介して、炎症等に関連すると考えられており、OA患者滑膜で発現が上昇すること(Bull Hosp Jt Dis. 2005;63(1-2):63-9)、CD9ノックアウト(KO)マウスを用いたOAモデルの一部では軟骨損傷が少ないなどの報告(Biomed Res.2016; 37(5):283-291)もありOAへの関与が示唆される。更に、炎症性サイトカイン刺激により軟骨細胞自身のCD9発現を誘導することをRT-PCR、細胞免疫染色で明らかにした。
    エクソソームを蛍光標識することにより軟骨細胞へのエクソソームの取り込みを確認した。ダイナミン阻害剤を用いるとエクソソームの取り込みがほとんど無くなったことから、エクソソーム取り込みの主たる経路はクラスリンを介したエンドサイトーシスであることを明らかにした。

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  • 適度なアルコール摂取による動脈硬化予防効果の分子メカニズム基盤の確立

    研究課題/領域番号:18K05488  2018年04月 - 2021年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    臼井 真一, 廣畑 聡, 柴倉 美砂子, 篠畑 綾子

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    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

    1.前年度に引き続き,HepG2細胞のHDL生合成におけるエタノールの影響を検討した。ゲルろ過クロマトグラフィによる解析ではエタノールにより培養上清中のHDL-コレステロールの増加傾向,HDL粒子径の大型化,LDLコレステロールの増加が見られた。これらの変化がどのようなメカニズムによるものなのか,HDL代謝に直接的に関与する蛋白質(ABCA1, HTGL, LCAT,CETPなど)についてウエスタンブロット解析を実施したが,これまでの検討ではエタノールによる明らかな変動は認められなかった。また,コレステロール代謝やLDL代謝の変化が間接的にHDL代謝へ影響を及ぼしている可能性を考え,SREBP2, CYP7A1, MTP, LDLレセプターなどの蛋白発現も分析したが,いずれも一定の傾向をもった結果が得られなかった。
    2.今年度は新たに動物実験を開始した。1%エタノールをSDラットに自由摂取させ,10週後に血清および各臓器を採取した。飼料と飲料の摂取量はコントロール群(水飲料)に比べエタノール摂取群で少ない傾向があったが,体重変化には有意差が見られなかった。肝臓組織はエタノールによる脂肪肝の発症は見られず,肝障害のマーカーである血清ALT,AST値もコントロール群と有意差がなく良好な結果であった。血清脂質分析では,エタノール摂取により総コレステロールの減少傾向が見られ,HDL-コレステロールは予想に反して減少傾向であった。血清アポE濃度およびHDL-アポE濃度は低下していた。HDLサブクラス解析では,アポE-rich HDLが減少傾向であった。脂質組成では,HDLの遊離コレステロール比率が減少している傾向が見られた。これらの結果は,アルコール摂取がHDL-コレステロール量だけでなく,クオリティーの変化に関与している可能性を示唆している。

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  • ハンセン病医療倫理学の創出に向けた学術的基盤の構築とカリキュラム開発

    研究課題/領域番号:18H03075  2018年04月 - 2021年03月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    近藤 真紀子, 亀岡 智美, 廣畑 聡, 兵藤 好美, 粟屋 剛, 竹田 芳弘, 齋藤 信也, 宮原 信明, 岡 久雄, 本村 昌文, 桑原 敏典, 大浦 まり子, 生田 由加利, 樋之津 史郎, 吉川 あゆみ, 真壁 五月

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    配分額:17160000円 ( 直接経費:13200000円 、 間接経費:3960000円 )

    ハンセン病は古来から差別や排斥の対象となり、明治以降は、らい予防法下で、強制収容・終生隔離の対象とされ、療養所内でも人権蹂躙のあった歴史を持つ。本プロジェクトの目的は、ハンセン病を医療教育の中で語り継ぎ、医療倫理について深く考えることのできる人材を育成できるよう、教育環境を整えることである。
    本年度は初年度であることから、まず、ハンセン病と医療倫理に関する研究の動向について、文献レビューを行った。その結果、ハンセン病の差別・排斥については、法学・社会学・歴史学・民俗学・優生学などの視点からの指摘はあるものの、医の倫理・医療倫理・看護倫理の視点からの指摘は少ないことが示唆された。
    次に、ハンセン病を語り継ぐための教材を作成した。教材には、ハンセン病を正しく理解するために必要な知識として、ハンセン病の病態生理、および、わが国におけるハンセン病の歴史を加えた。さらに、ハンセン病者がらい予防法下でどのような苦悩を体験したのかを理解するために、ハンセン病回復者のライフレビュー、すなわち、誕生から、ハンセン病の診断をうけて療養所に入所し、療養者内で人生のほとんどの時間を過ごし、老境に至った現在までの、生涯にわたる人生の回想を加えた。
    これらの教材を元に、コメディカル系学部1年生、看護系学部2年生・4年生、医療系以外の大学生、一般社会人などを対象に授業展開を行った。現在は、これらの学生の授業評価および授業をとおして学びについて分析を行っている。今後は、これらの結果に基づき、教材の加筆修正を行い、公開を目指す予定である。

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  • 変形性関節症の新規診断法リキッドバイオプシーの開発

    研究課題/領域番号:17K19727  2017年06月 - 2019年03月

    日本学術振興会  科学研究費助成事業 挑戦的研究(萌芽)  挑戦的研究(萌芽)

    廣畑 聡, 大月 孝志, 臼井 真一, 稲垣 純子

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    配分額:6500000円 ( 直接経費:5000000円 、 間接経費:1500000円 )

    変形性関節症には適切な早期診断法がない。リキッド・バイオプシーは新たな早期診断法となる可能性がある。
    ラット膝関節の前十字靭帯及び内側側副靭帯を切離し、内側半月板を切除した変形性関節症手術モデルを作成し、経時的にそれぞれ関節液および末梢血液を採取した。サンプルからエクソソームを含む小胞成分を精製し、粒子径を測定した。次にエクソソーム中に含まれているRNA成分を定量した。一連の結果から、変形性関節症早期では関節液よりも血液によるリキッド・バイオプシーを目指すことが妥当であると考えられた。さらに、血液中のエクソソーム内のRNA解析結果から超高感度測定系が必要であることが明らかとなった。

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  • 関節軟骨の情報伝達性エクソソーム網羅的解析と変形性関節症の新たな治療開発

    研究課題/領域番号:17H04313  2017年04月 - 2021年03月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    廣畑 聡, 冨田 秀太, 大月 孝志, 渡辺 彰吾, 西田 圭一郎

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    配分額:17160000円 ( 直接経費:13200000円 、 間接経費:3960000円 )

    近年、エクソソームなどの細胞外に分泌される小胞がmicroRNAやタンパクなどの情報を他の細胞へ伝える細胞間情報伝達機構として注目されている。
    本研究の目的は、変形性関節症で重要な働きをするADAMTSや関連分子を標的とするmicroRNAが含まれるエクソソームを分離し、microRNAを含んだエクソソームがどの様に細胞に取り込まれて機能するのかを明らかにすることでその役割を統合的に解析することである。
    変形性関節症(OA)早期に重要なアグリカナーゼ(ADAMTS)を標的とするmicroRNA、すなわち、OAではたらく候補microRNAを複数個同定することに成功した。さらに、候補microRNAの遺伝子導入実験にも成功してADAMTSやMMPに作用することも確認できた。
    実際に、これまでに報告のないmicroRNA-Xを軟骨用細胞に対して強制的に発現させると、ADAMTSのmRNAを90%抑制することを定量PCR法にて見出した。
    エクソソームはがん細胞や炎症細胞から多く分泌されているが、実際には正常細胞も分泌しており、組織の恒常性維持に関わる機能を担っていることが考えられた。エクソソームの細胞に取り込まれるメカニズムは、細胞選択性や疾患特異性を表現している可能性がある。
    このメカニズムの同定は、エクソソームの情報伝達機構を理解する上で、細胞生物学的にも大きなインパクトを与え、波及効果が期待できる。この重要課題を解決するために『エクソソームの表面膜成分』と『細胞側の取り込みタンパク』の2つを解明する、新たな研究を展開すべき状況となった。

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  • ドラッグ・リポジショニングによる変形性関節症の新規治療薬開発

    研究課題/領域番号:17K11009  2017年04月 - 2020年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    ハティポール オメル・ファルク, 大月 孝志, 稲垣 純子, 廣畑 聡

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    配分額:4550000円 ( 直接経費:3500000円 、 間接経費:1050000円 )

    本研究では変形性関節症に重要なEMC分解酵素に着目し,EMC分解酵素の合成を抑制することで軟骨基質の破壊を抑制できる化合物を探索しようと考えた。理化学研究所が提供している400種類のパイロットライブラリーをスクリーニングし,ECM分解酵素の発現抑制効果を検討した結果、化合物Xは,炎症性サイトカインであるIL-1βによる炎症で惹起された,MMP3・MMP13・ADAMTS4・ADAMTS9という4種類の細胞外マトリックス分解酵素のmRNA発現を有意に抑制した。また炎症を促進する役割を持つ酵素COX2の発現もまた有意に抑制し、化合物XはOAの治療に有効である可能性があると考えた。

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  • 関節リモデリングにおけるmicroRNAとADAM12の発現調節機構の解明

    研究課題/領域番号:17K11010  2017年04月 - 2020年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    西田 圭一郎, 大月 孝志, 廣畑 聡

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    配分額:3900000円 ( 直接経費:3000000円 、 間接経費:900000円 )

    Adam12は、Wild type ATDC5細胞の分化過程において、Col10a1発現に先発って発現が上昇した。一方、Adam12-KO ATDC5細胞では、軟骨分化開始後、Runx2、Col10a1、およびX型コラーゲン蛋白発現が亢進し、Igf-1発現は抑制された。Wild type ATDC5細胞では、TGF-β1刺激により、Adam12およびIgf-1の発現が亢進し、Runx2発現は抑制された。一方で、Adam12-KO ATDC5細胞では、TGF-β1刺激による変化は抑制された。Adam12の過剰発現は、ATDC5細胞におけるIgf-1の発現亢進とRunx2の発現抑制をもたらした。

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  • microRNAとエクソソーム解析によるメカニカルストレスの関節軟骨への作用解明

    研究課題/領域番号:16K10905  2016年04月 - 2019年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    大月 孝志, 古松 毅之, 西田 圭一郎, 廣畑 聡, 品岡 玲

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    配分額:4810000円 ( 直接経費:3700000円 、 間接経費:1110000円 )

    関節液を遠心、酵素処理しエクソソーム(EVs)の精製する方法を確立した。更に軟骨細胞へのEVs添加試験系を確立しマトリックス成分、マトリックス分解酵素、ヒアルロン酸分解酵素mRNAの発現変化をRT-PCR法を用いて解析した。 軟骨細胞のEVs取り込み機構を解析し、クラスリンの関与するエンドサイトーシスであることを明らかにした。
    軟骨細胞に対しメカニカルストレスを与え、炎症性サイトカインで誘導されるマトリックス分解酵素発現を抑制する可能性のあるmicro RNAを複数同定した。これらmicro RNAのタンパクレベルでのプロテオグリカン分解酵素産生抑制、ヒアルロン酸分解因子産生抑制を確認した。

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  • 生活習慣病におけるアポE含有HDLの役割

    研究課題/領域番号:15K01715  2015年04月 - 2018年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    臼井 真一, 廣畑 聡, 篠畑 綾子

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    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    本研究では,血清アポE含有HDLの定量測定法を開発し,肥満モデルマウスでアポ含有HDLが増加することを示した。臨床検体の検討では,重回帰分析により,肥満に深く関わる中性脂肪やアディポネクチンがアポE含有HDL-コレステロールの有意な予測因子であることを明らかにした。しかし,脂肪細胞の培養実験では,アポE含有HDLが脂肪蓄積に関与するデータは得られなかった。一方,肝細胞の培養実験では高グルコース培地によりアポE含有HDLの生成が増加し,細胞内へのグルコース取り込みがアポE含有HDLの生成に深く関与していることが示唆され,糖代謝とアポE含有HDLの生成との関連において今後新たな展開が期待される。

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  • 軟骨特異的プローブによる関節軟骨in vivo造影と定量評価システムの確立

    研究課題/領域番号:15K15551  2015年04月 - 2017年03月

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究  挑戦的萌芽研究

    大橋 俊孝, 廣畑 聡, 大月 孝志, アゾーディ アティラ, 西田 圭一郎, 加来田 博貴

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    配分額:3640000円 ( 直接経費:2800000円 、 間接経費:840000円 )

    Ke4-TIBに加えて新規軟骨イメージングプローブ2Ke2-TIBの創出とラット変形性関節症モデルによる、in vivo造影とCT撮像による定量評価を試みたが、理想的な条件設定は完了していない。Ke4-TIBについては特許が2017年3月24日に成立した。プローブ開発と並行して、将来マウス関節軟骨変性モデルが研究へ使用されることを想定して、新規関節軟骨変性モデルの作製にとりかかった。軟骨に豊富に発現している細胞外マトリックス遺伝子(A遺伝子)のFloxマウスをRosa26-cre ERTマウスと交配させた。生後1週よりタモキシフェン投与を開始し、未投与群に比べ、低身長と関節軟骨異常を認めた。

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  • 分子生物学的解析に基づく変形性膝関節症へのリハビリテーション治療の検討

    研究課題/領域番号:26750185  2014年04月 - 2017年03月

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    熊岸 加苗, 廣畑 聡, 大月 孝志, 品岡 玲, 河村 顕治, 酒井 孝文

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    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

    変形性膝関節症(OA)において、膝関節内へのヒアルロン酸投与と運動療法の効果に関する解析を生化学的・組織学的に行った。
    これらの併用療法が膝関節滑液中の炎症性サイトカインやMMP13を減少させることがわかった。さらに、同併用療法の関節軟骨組織への影響を観察すると、膝関節内にヒアルロン酸を投与した場合、運動負荷のみを行ったものと比べて軟骨変性が著明に軽減していることがわかった。
    本研究より、ヒアルロン酸に軟骨の保護効果があることが証明された。

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  • 腫瘍内圧とがん血管、リンパ管、細胞外マトリックスのメカノバイオロジー

    研究課題/領域番号:26350500  2014年04月 - 2017年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    稲垣 純子, 成瀬 恵治, 廣畑 聡

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    配分額:4810000円 ( 直接経費:3700000円 、 間接経費:1110000円 )

    マトリックス分解酵素で血管・リンパ管新生抑制作用を持つADAMTS1は、低酸素や血流等のメカニカルストレスでも発現誘導される。今回は腫瘍組織における腫瘍内圧変化によるADAMTS1の発現制御メカニズムを解析し腫瘍内圧との関連性を検討した。宿主由来のADAMTS1は、主に新生血管内皮細胞から発現されていることが明らかになった。腫瘍血管の脆弱性、希薄化、腫瘍内圧の変化に関与している可能性が示唆された。

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  • 関節破壊を制御するマイクロRNAの統合的解析と軟骨における機能解析

    研究課題/領域番号:26293338  2014年04月 - 2017年03月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    廣畑 聡, 伊藤 佐智夫, 成瀬 恵治, 西田 圭一郎, 大月 孝志, 二宮 善文

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    配分額:16250000円 ( 直接経費:12500000円 、 間接経費:3750000円 )

    本研究は変形性関節症の細胞外マトリックス分解に中心的役割を持つアグリカナーゼの遺伝子発現レベルがmicroRNAによってどう制御されるかを統合的に解析し、その作用メカニズムを明らかにした。microRNAの標的遺伝子を探索するために、複数のデータベースを使い候補となる遺伝子を絞り込んだ。今回の研究によって、変形性関節症の細胞外マトリックス破壊に役割を持つ可能性のある新たなmicroRNAを同定し、機能を明らかにすることができた。

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  • 変形性関節炎におけるエンドサイトーシスの新たな機能とその重要性

    研究課題/領域番号:26670665  2014年04月 - 2016年03月

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究  挑戦的萌芽研究

    廣畑 聡, 山田 浩司, 大月 孝志

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    配分額:3640000円 ( 直接経費:2800000円 、 間接経費:840000円 )

    アグリカンを分解するアグリカナーゼのうち、ADAMTS5が重要であることはノックアウトマウスを使った実験で証明されているがその制御機構は充分に解明されていない。我々は、軟骨様細胞であるOUMS-27細胞においてエンドサイトーシスが起こっていることを明らかにした。さらにエンドサイトーシス関連分子であるLRP-1を検討したところ、OUMS-27をIL-1β刺激した際にLRP-1が切断されることを発見した。一方でLRP-1のアンタゴニストとして働くとされるReceptor-associated protein (RAP)のmRNA発現レベルはIL-1βによって変化しないことが明らかとなった。

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  • ヒアルロン酸の変形性関節炎アップストリーム治療薬としての新展開と関節保護作用

    研究課題/領域番号:25462372  2013年04月 - 2016年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    大月 孝志, 廣畑 聡, 西田 圭一郎, 藤渕 航, 篠畑 綾子, 草地 省蔵, 二宮 善文

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    配分額:4940000円 ( 直接経費:3800000円 、 間接経費:1140000円 )

    1)ヒアルロン酸(HA)によるサイトカイン誘導性アグリカナーゼ発現抑制micro RNAの検出
    分解系酵素を制御すると考えられる複数のmiRNAを検出した。2) OAモデルラットへのHA投与の長期効果 長期(9w)投与試験では有意な軟骨損傷抑制効果は見られたが、効果は中期間より減少した。3) メカニカルストレスのヒアルロン酸受容体遺伝子発現への影響 軟骨細胞のHA受容体CD44、ICAM1mRNA発現変動は見られなかった。4)メカニカルストレスによるマトリックスタンパク発現への影響 弱いメカニカルストレス刺激で軟骨細胞のマトリックスタンパク、アグリカン、2型コラーゲン遺伝子発現が増大した。

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  • ADAMTS4とTGF-βの制御による左室リモデリングへの作用

    研究課題/領域番号:25461110  2013年04月 - 2016年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    草地 省蔵, 廣畑 聡, 小川 弘子

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    配分額:5070000円 ( 直接経費:3900000円 、 間接経費:1170000円 )

    本研究の目的は、細胞外マトリックス分解酵素ADAMTSの左室リモデリングおよび線維化における役割とその制御メカニズムを検証することである。本研究では、まず基質を互いに共有しともにアグリカナーゼとして知られるADAMTS4とADAMTS5のダブルノックアウトマウスを作成した。ダブルノックアウトマウスは正常に産まれた。次にApoEノックアウトマウスとのトリプルノックアウトマウスを作成した。トリプルノックアウトマウスに高脂肪食を負荷し、動脈硬化巣形成への作用を検討したところ、ApoE単独ノックアウトマウスと比較して有意な差を認め、新たな創薬へと結びつく興味ある知見が得られた。

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  • 変形性膝関節症における機械的刺激の効果に関する生化学的解析

    研究課題/領域番号:24700531  2012年04月 - 2014年03月

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    熊岸 加苗, 大月 孝志, 廣畑 聡, 河村 顕治, 品岡 玲, 酒井 孝文

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    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

    変形性関節症の保存的治療でのヒアルロン酸(HA)関節内投与と機械的刺激を併用した場合の治療効果について検証した。整形外科受診の変形性膝関節症患者を対象に、HA投与・運動刺激の有無にて治療群分けを行い、治療開始後1ヵ月での効果を評価した。
    結果、高分子HA投与後に一定の運動刺激を行った変形性膝関節症患者群においては、治療後の関節破壊マーカーに有意な改善が見られることがわかった。さらにそれは、進行期群と比べて初期群において、より治療効果が高いことも発見した。

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  • 関節破壊を制御する転写因子とマイクロRNAの誘導機構とその治療応用

    研究課題/領域番号:23390366  2011年04月 - 2014年03月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    廣畑 聡, 二宮 善文, 成瀬 恵治, 西田 圭一郎, 大月 孝志, 小川 弘子

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    配分額:19110000円 ( 直接経費:14700000円 、 間接経費:4410000円 )

    本研究の目的は変形性関節炎(OA)の細胞外マトリックス分解に中心的な役割を果たす切断酵素アグリカナーゼの遺伝子発現を制御するmicroRNAと転写因子群の発現制御を明らかにすることである。細胞伸展刺激装置を用いた軟骨様細胞実験系において、メカニカルストレスによる転写因子の発現誘導を解析した。転写因子においてはHIF-2は刺激によってそれほど上昇顕著ではなく他の転写因子の関与が大きいと考えられた。microRNAに関しては、サイトカイン刺激とメカニカルストレス刺激による反応性を網羅的に解析した。既報のmiR-140を含め、microRNA変動が層別化できることが初めて明らかとなった。

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  • 脳小血管障害における基底膜の役割

    研究課題/領域番号:23390348  2011年04月 - 2014年03月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    二宮 善文, 米澤 朋子, 大橋 俊孝, 廣畑 聡, 大塚 愛二, 幡中 邦彦, 斎藤 健司, 百田 龍輔, 小川 弘子, 稲垣 純子

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    配分額:19240000円 ( 直接経費:14800000円 、 間接経費:4440000円 )

    血液-脳関門の破綻や脳小血管の出血に基底膜の機能の異常が関与すること、及び、その分子機構を明らかにすることを目的とした。我々は、マウス静脈内に腫瘍壊死因子(TNFα)を投与し、血液-脳関門の破綻を誘導する脳炎モデルを作製した。そして血液-脳関門の破綻および基底膜の主成分であるIV型コラーゲンの変化についてWestern blot法および免疫組織染色法を用いて継時的に解析を行った。解析の結果、継時的にIV型コラーゲンは限定的に分解され、血液-脳関門の破綻と関連性のあることが示唆された。

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  • ADAMTSメタロプロテアーゼによる血管・リンパ管新生研究の新展開

    研究課題/領域番号:23112511  2011年04月 - 2013年03月

    日本学術振興会  科学研究費助成事業 新学術領域研究(研究領域提案型)  新学術領域研究(研究領域提案型)

    廣畑 聡

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    配分額:8710000円 ( 直接経費:6700000円 、 間接経費:2010000円 )

    ADAMTS1(a disintegrin and metalloproteinase with thrombospondin motifs1)はがんの悪液質に関連する遺伝子としてクローニングされた細胞外マトリックス(ECM) 分解酵素である。我々は全長ADAMTS1とプロテアーゼドメインを欠失したADAMTS1(delta-ADAMTS1)の二つのコンストラクトを作成した。
    Tube formationアッセイでは二つのコンストラクト共に有意に血管新生を阻害した。さらに二つのコンストラクトは共にHUVECの増殖を阻害した。一方、平滑筋細胞や線維芽細胞に対しては阻害効果を認めなかった。同様にフローサイトメトリーによる解析でAnnexin-V陽性細胞数はHUVECで有意に増加していたが、他の細胞では認めなかった。担がんマウスを用いた遺伝子導入治療において、二つのADAMTS1はいずれも抗腫瘍増大効果を発揮した。腫瘍内血管数は有意に減少しており、ADAMTS1治療群では腫瘍内の血管に活性型caspaseのシグナルを認めた。以上より、ADAMTS1はプロテアーゼドメイン非依存的に血管内細胞にアポトーシスを起こし、腫瘍の成長を抑制することが明らかとなった。
    さらに、アデノウイルスに全長ADAMTS1を組み込み、アデノウイルス治療によるリンパ管内皮細胞(HMVEC-dLy)への効果を検討した。VEGFC刺激したHMVEC-dLyはVEGF-R3のリン酸化を起こすが、アデノADAMTS1はリン酸化を抑制した。またアデノウイルスによりADAMTS1を導入したMDA-MB231乳がん細胞株はコントロールと比べてHMVEC-dLyの遊走を抑制した。
    ADAMTS1は血管新生・リンパ管新生をそれぞれのメカニズムにより阻害することを明らかにした。

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  • 細胞外マトリックスによるがん血管新生、リンパ管新生制御のメカノバイオロジー

    研究課題/領域番号:23612004  2011年 - 2013年

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    稲垣 純子, 廣畑 聡, 二宮 善文, 成瀬 恵治

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    配分額:5460000円 ( 直接経費:4200000円 、 間接経費:1260000円 )

    ADAMTS1はマトリックス分解酵素であり強力な血管新生抑制作用を持つ。ADAMTS1のリンパ管新生への効果と、担がんマウスモデルにおけるがん組織中の内圧と腫瘍増殖、リンパ管新生の関係について検討した。リンパ管内皮細胞に強制発現させたADAMTS1は、VEGFCと複合体を形成しVEGFR3のシグナル伝達を阻害することでリンパ管新生を抑制することが明らかになった。また、内圧の増大する腫瘍にVEGFCを投与しリンパ管を形成させると、腫瘍の増大が抑制された。さらに、伸展刺激がADAMTS1やリンパ管新生関連遺伝子の発現に影響を与えている可能性が示唆された。

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  • ドキシサイクリン:腎虚血再還流障害の新治療戦略

    研究課題/領域番号:23791758  2011年 - 2012年

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    荒木 元朗, 廣畑 聡, 二宮 善文

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    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

    マウス腎虚血再還流モデルを用いてドキシサイクリンによる腎保護効果を確認した。対照群に比べドキシサイクリン投与群では腎虚血後 24 時間の血清クレアチニンが低下していた。組織学的にもドキシサイクリン投与群で尿細管腔の拡張の程度が軽減しており腎障害の軽減が確認された。このメカニズムとしてはドキシサイクリンによる matrix metalloproteinases (MMPs)阻害による腎組織内好中球浸潤の減少傾向が寄与していることが示唆された。

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  • ヒアルロン酸による関節破壊抑制のメカニズム解析

    研究課題/領域番号:22591687  2010年 - 2012年

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    大月 孝志, 西田 圭一郎, 廣畑 聡, 二宮 善文

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    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    ヒアルロン酸をサイトカイン刺激軟骨細胞に添加することで軟骨基質分解酵素の発現が抑制され、その作用は使用濃度、分子量に比例して増加することを細胞レベルで確認した。また、手術によるラット変形性膝関節症モデルの膝へのヒアルロン酸投与試験においても同様に濃度依存的、分子量依存的な関節保護効果を確認した。ヒアルロン酸の早期変形性関節症治療薬としての可能性を見出した。

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  • 心筋梗塞後リモデリングにおけるADAMTS4の役割と治療応用

    研究課題/領域番号:20590867  2008年 - 2010年

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    草地 省蔵, 三好 亨, 廣畑 聡, 小川 弘子

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    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    心筋梗塞におけるADAMTS4の発現を検討した。梗塞心の梗塞辺縁領域に強いADAMTS4の発現誘導を認めた。次にADAMTS4ノックアウトマウスを用いて解析を行った。まず、ADAMTS4ノックアウトマウスの心臓形成には明らかな異常は認めなかった。次にADAMTS4ノックアウトマウスを用いて心筋梗塞を作成し、野生型と比較した。梗塞後の生存率には有意な差はなく、炎症細胞の浸潤度および梗塞後の心機能にも有意な差は見られなかった。以上より、19ある他のADAMTSメンバーがADAMTS4ノックアウト心筋梗塞マウスにおいて代償的に働いている可能性が示唆された。

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  • 関節炎におけるアグリカナーゼ制御機構と変形性関節症早期診断・関節保護治療への応用

    研究課題/領域番号:20390399  2008年 - 2010年

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    廣畑 聡, 二宮 善文, 成瀬 恵治, 大橋 俊孝, 西田 圭一郎

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    配分額:19630000円 ( 直接経費:15100000円 、 間接経費:4530000円 )

    同意が得られた関節炎患者におけるADAMTS9のSNPを解析した。ADAMTS9のプロモーター解析でNF-κBの結合を同定した。関節炎患者由来細胞に周期性伸張刺激を加えるとADAMTS1,4,5,9はいずれも異なる発現誘導パターンを示した。COL1A1の発現増強とともにインテグリンの関与を明らかにした。軟骨細胞にメカニカルストレス刺激を加えるとMMP-13およびADAMTS-5が増加し、RUNX-2とp38MAPKが関与していた。ラット変形性関節炎モデルを作成し解析を行った。

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  • 虚血再還流障害に関する研究―ドキシサイクリンは50年の沈黙を破れるか

    研究課題/領域番号:20791111  2008年 - 2009年

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    荒木 元朗, 河内 啓一朗, 廣畑 聡, 二宮 善文

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    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

    マウス腎虚血再還流モデルを確立した。8-12週のB6マウスを麻酔下に開腹し、腎動静脈を一括クランプする。電灯・heatpadを用いてマウスの腹腔内温度を32℃に保ち、45分後に腎動静脈を開放(unclamp)する。腎機能の評価は24時間ごとに血清クレアチニンを測定した。腎組織が必要な場合その時点でマウスをsacrificeし、標本を保存し、組織の比較検討を行った。ドキシサイクリンによる腎虚血再還流障害が軽減されていることを確認した(これまで報告がない)。

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  • 内皮細胞由来ADAMTS1の虚血バイオマーカーとしての可能性

    研究課題/領域番号:19659142  2007年 - 2008年

    日本学術振興会  科学研究費助成事業 萌芽研究  萌芽研究

    廣畑 聡, 臼井 真一, 三好 亨, 草地 省蔵

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    配分額:3100000円 ( 直接経費:3100000円 )

    ADAMITS1は超急性期虚血においてのみ強く内皮及細胞から分泌され、時間が経過した急性虚血では分泌されない性質を持つ。この実験的事実からADAMTS1は超急性期虚血でのみ内皮細胞に特異的に誘導され分泌されるタンパクであると考えた。そして、この特性を利用して、ADAMTSIを超急性期の虚血を検出するバイオマーカーとして利用できるのではないかと仮説を立て、これを証明するために下記の実験を行った。
    1.ADAMTS1に対するELISA系の確立
    市販されている精製ヒトADAMTS1タンパクを用いてADAMTS1のサンドイッチELISA法を確立した。各社より販売されている抗ヒトADAMTS1抗体および独自に作成したモノクローナル抗体を用いてそれぞれ反応性を検討した。もっとも反応性のよかった抗体を以後の検討に利用することとした。
    2.低酸素組織におけるADAMTS1の血清変動
    心筋梗塞ラットより虚血後、1,3,6,24時間後に血液を採取し、血漿を分離した。経時的なADAMTS1の血漿中レベルの変動について解析を行う予定であったが、血漿とは反応性が不良であったためか、測定感度レベルより低値であった。
    3.ADAMTS1の虚血バイオマーカーとしての可能性
    ADAMTS1が本当に超急性期虚血バイオマーカーとして利用可能かどうかを、以下の2群において血清中のADAMTS1変動を測定することにより検討する。
    (1)急性心筋梗塞および24時間以内の狭心症患者
    (2)胸痛があるが急性心筋梗塞や狭心症のない患者
    インフォームドコンセントの元に(1)急性心筋梗塞および24時間以内の狭心症患者から血清を採取した。心筋梗塞入院時および再灌流治療後4,8,12時間後にそれぞれ血清を採取し、血清ADAMTS1レベルの時間的推移をELISA法にて検討した。

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  • 細胞膜透過ペプチドベクターを用いたsiRNA溶出ステントの開発

    研究課題/領域番号:18500364  2006年 - 2007年

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    大橋 俊孝, 廣畑 聡, 松井 秀樹, 新留 琢朗, 森 浩二

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    配分額:4020000円 ( 直接経費:3600000円 、 間接経費:420000円 )

    1.ラット血管平滑筋細胞を使ったコーティング法の最適化(大橋・新留)
    モデルsiRNA薬剤(蛍光ラベルsiRNA,)導入のためのステント表面修飾用最適コーティング法の検討をおこなった。Tiの酸化膜に硫酸化グリコサミノグリカン(GAG)を結合させるコーティングを選択した。さらに、硫酸化GAGに塩基性PTDペプチドが結合することを水晶発信子(QCM)法により定量した。さらに、細胞を播種し細胞内取り込み量を蛍光量にて定量して評価したが、コントロールと比して、取り込み量の差を十分に認められなかった。播種して接着する時間までのHeparinへの結合安定性・持続性が不十分であると想定された。
    2.ラット血管平滑筋細胞を使ったsiRNA導入効果の確認(大橋・松井)
    siRNA導入が機能的に十分発現・機能抑制に働いているかを確認する。サイトカイン誘導により、再狭窄時に増殖する内膜平滑筋細胞から様々な遺伝子が発現誘導されてくる。
    ターゲットとしたのは、メタロプロテアーゼの一種のADAM-TS遺伝子である。IL-1刺激により発現が6時間後に上昇する。プローモーター上流域に転写因子NFAT結合部位が存在し、NFAT阻害剤(1 □M)で、ADAM-TS遺伝子発現が低下した。NFATの脱リン酸化と核内移行が再狭窄遺伝子発現に関与することがわかった。
    3.ラット血管再狭窄モデルにおけるsiRNAステントによる治療 (廣畑・森)
    Tiステントを入手しステントクリンプで工夫して折りたたみ、バルーンカテーテルに装着しラット総腸骨動脈への挿入実験を行った。このプロトタイプは極小化と動作柔軟性がまだ不十分であるため、血管障害を引き起こし、留置成績は大動脈より良くなかった。

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  • 新規アグリカナーゼの関節炎早期における誘導メカニズムとその役割・診断的応用

    研究課題/領域番号:18390416  2006年 - 2007年

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    廣畑 聡, 二宮 善文, 西田 圭一郎, 成瀬 恵治, 小川 弘子

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    配分額:17180000円 ( 直接経費:15500000円 、 間接経費:1680000円 )

    1:アグリカナーゼ誘導に関わる細胞内分子メカニズム
    Wister系胎児ラットの膝関節から軟骨細胞を分離培養し、メカニカルストレスを加え、ストレス刺激時のアグリカナーゼ発現誘導を調べた。最終的に7%伸展(0.33または0.5Hz)で刺激後、0.5,2,6,12時間後にRNAを抽出し、各アグリカナーゼ発現の変化を検討したところ、アグリカナーゼ-2であるADAMTS 5は殆ど発現レベルに変化を生じないのに対して、ADAMTS1,4,9はいずれも発現が上昇している結果が得られた。
    次にADAMTS9の発現誘導に関わる細胞内転写因子およびその結合部位に関する研究を行った。まず、ヒトADAMTS9のプロモーター部位をgenomic PCRにて得ることに成功した。異なった長さのDNAをルシフェラーゼアッセイ用のベクターに組み込んでコンストラクトを作成しルシフェラーゼアッセイを行い最もプロモーター活性の強いコンストラクトを決定した。
    2:ラットOAモデルおよびマウス成長軟骨におけるADAMTS9発現動態の解析
    雄性Wisterラット(200-300g)を用いて変形性関節炎モデルを作成し免疫染色を行った。関節破壊が進行しているステージではADAMTS9陽性細胞を多数認めたが、一方進行した時期ではむしろADAMTS9陽性細胞は減少していた。
    次に、0週,7週,14週齢雄ICRマウスにおけるADAMTS-9のmRNA発現の検討を行った。マウス脛骨成長軟骨において、ADAMTS-9は成熟軟骨細胞層で一部陽性、肥大軟骨細胞においては、mRNAレベルで強く発現していた。成長軟骨における軟骨分化過程において、軟骨細胞が肥大化する際に、周辺のマトリックスを分解する手段の一つとしてADAMTS-9が関与する可能性があると考えられた。

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  • 「良い血管基底膜」が糖尿病網膜症を抑制する-血管内皮特異的ラミニンの役割-

    研究課題/領域番号:16591755  2004年 - 2005年

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    草地 省蔵, 二宮 善文, 廣畑 聡, 白神 史雄

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    配分額:3800000円 ( 直接経費:3800000円 )

    糖尿病網膜症は、新生血管の増生と共に、出血などの血管透過性の脆弱性及び亢進を伴う。本研究の目的は糖尿病網膜症の新生血管増生に関する血管基底膜の役割を明らかにし、血管基底膜成分ラミニンの制御による異常新生血管の抑制を検討することである。具体的には、血管基底膜と血管透過性の維持性に注目し、基底膜の構成成分であるラミニン・IV型コラーゲンの糖尿病網膜症進展への影響を検討した。
    1.糖尿病網膜症を規定する基底膜成分の破壊状況
    ストレプトゾトシン(STZ)180mg/kgを腹腔内投与し、糖尿病マウスを作成した。静脈血中の血糖値を測定し、250mg/dl以上の高血糖状態が持続していることを確認した。糖尿病網膜症における基底膜の破壊状況を解析するために、血管透過性を指標に、エバンスブルーおよび蛍光デキストラン、フルオレセインをそれぞれ糖尿病マウス対照マウスに投与し、眼底写真を撮影、あるいは網膜展開を行い検討した。その結果、明らかにleakyな状態である血管は網膜には確認されなかった。
    2.網膜における基底膜成分の変動解明
    本動物モデルの網膜において、IV型コラーゲンα1-α6鎖までの特異的抗体およびラミニンα4鎖及びα5鎖に対する特異的抗体を用いて、免疫染色を行い、網膜血管における局在を検討した。網膜血管基底膜では、IV型コラーゲンα1α2鎖の発現が見られた。また内境界膜ではα1α2鎖に加えて、α5α6鎖の局在も確認された。一方、色素上皮層を裏打ちする基底膜成分では、α1α2に加えて、α3α4α5鎖が存在することが明らかとなった。
    3.糖尿病網膜症を規定する基底膜成分の変化が与える網膜症の進展への関与
    糖尿病網膜症動物モデルに対し、基底膜成分が変化した場合に、網膜症の進行に影響を与えるかに関しては、ヒト病態に即した糖尿病網膜症モデル動物の作成が最重要と考えられた。

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  • 新しい基底膜様構造フラクトンの機能と脳室下帯神経幹細胞の分化制御

    研究課題/領域番号:16390048  2004年 - 2005年

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    二宮 善文, 米澤 朋子, 大橋 俊孝, 廣畑 聡, 大塚 愛二, 内藤 一郎

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    配分額:14400000円 ( 直接経費:14400000円 )

    脳実質内の毛細血管の連続した構造体fractoneを構成する分子の解析を行なった。また、マウス脳室下帯より神経幹細胞の同定と分離、さらにはその分化の制御機構を解析することを試みた。
    [1]新しい基底膜様構造フラクトンの分子細胞生物学的解析
    基底膜分子に特異的抗体を用いて免疫染色をすると、fractone構造にはラミニン、IV型コラーゲン等の分子が存在することが明らかとなった。しかし、それらの各鎖の分布には偏りが認められた。基底膜の周りに存在するfibronectinはfractone特有の染色像を示さなかった。脳や脊髄におけるfractoneの分布について調べたところ、脳室のほぼ全周に分布していたが、第三脳室の一部、第四脳室の一部では存在していなかった。また、このfractone構造は生後すぐの脳室周囲では観察されず、生後7日目から現れはじめ、生後14日目では脳室の外側壁に偏った分布を示した。さらに、特異抗体を用い免疫電子顕微鏡による解析を行ない、fractone構造に基底膜分子が存在することを認めた。
    [2]マウス脳室下帯より神経幹細胞の同定と分離
    成体マウス脳室下帯より神経幹細胞の分離を試みた。分離した神経幹細胞の基本的培養条件の設定を行い、bFGFなどのサイトカインを付加した接着性基質上での単層培養条件において、ニューロンへの分化誘導、アストロサイトへの分化誘導を試みた。さらに、マトリックス基質の調整のための基礎的な実験を行なった。
    [3]in vitro細胞培養系を用いた細胞外マトリックスによる神経幹細胞の分化制御
    成体マウスと胎児期マウスの側脳室壁神経幹細胞の分離を行い、安定したneurosphereを得ることができるようになった。また、増殖因子の除去を行ってから単層培養を行ない各種に基質上で細胞の分化誘導の解析の条件設定ができるようになった。

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  • 細胞外基質による血管前駆細胞の分化誘導-血管内膜増殖阻害の試み-

    研究課題/領域番号:15591344  2003年 - 2004年

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    村上 充, 佐田 政隆, 廣畑 聡, 二宮 善文

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    配分額:3700000円 ( 直接経費:3700000円 )

    1)血中血管前駆細胞の分離・培養 ヒト静脈血より血管前駆細胞を培養する方法を確立した。静脈血より単球をHistropaque-1077で分離後、growth factorを添加したEGM-2 mediumにてfibronectin-coated dishで培養。7日目に細胞をトリプシン処理しDiI acLDL、UEA-1での染色、VEGFR2、CD31、CD34にてフローサイトメトリー(FCM)を行った。ほとんどの細胞でDiI acLDL、UEA-1がdual positiveであり、またFCMでVEGFR2、CD31の発現増強がみられた。以上より、末梢血中の単球が血管内皮前駆細胞(endothelial progenitor cell ; EPC)へ分化誘導されていることが確認できた。
    2)血管内皮前駆細胞の細胞外基質への接着の検討 上記のように分化誘導した7日目の血管内皮前駆細胞を用いて、様々な細胞外マトリックスに対する接着について検討した。ラミニン1、ラミニン8、ラミニン10、I型コラーゲン、IV型コラーゲンを96-wellにコートして、1時間のadhesion assayを行った。結果、ラミニン10に対しての接着が最もよく、ついでラミニン8>ラミニン1>IV型コラーゲン>I型コラーゲンの順であった。
    3)血管内皮前駆細胞のマトリックスメタロプロテアーゼ分泌能の検討 様々な細胞外マトリックスの上で、EPCのマトリックスメタロプロテアーゼ-2(MMP-2)分泌能に違いがあるかについて検討した。ラミニン1、ラミニン8、ラミニン10、I型コラーゲン、IV型コラーゲンを96-wellにコートして7日目のEPCを再プレート。FBS(-)のmediumにて48時間培養後、medium中のMMP-2濃度をELISAで測定した。EPCはMMP-2をすべての細胞外マトリックス上で分泌しており、特にラミニン8、I型コラーゲンで多くのMMP-2分泌が認められた。

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  • 血管新生を制御するマルチプレキシンコラーゲンを用いた肝癌の診断と治療

    研究課題/領域番号:15659170  2003年 - 2004年

    日本学術振興会  科学研究費助成事業 萌芽研究  萌芽研究

    二宮 善文, 米澤 朋子, 廣畑 聡

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    配分額:2800000円 ( 直接経費:2800000円 )

    血管新生を抑制するマルチプレキシンコラーゲンの性質を調べる意味で、以下の実験を行い、結果を得ることが出来た。マルチプレキシンコラーゲンの一つであるXVIII型コラーゲンは、そのカルボキシル末端の約250アミノ酸残基のNCドメインの中にはエンドスタチンとよばれ、腫瘍の周囲の血管新生を抑制することが1997年に初めて報告されてから、有望な抗がん作用を示す薬剤になりうる可能性を秘めていると思われて来た。しかしながら、いくつかの研究グループはその部分のペプチドに再現性を認めず、その作用機序を含め未解決の部分は多い。そこで、今回私どもは、XVIII型コラーゲンを多く産生する肝臓細胞株を探し出し、それをヌードマウスに打つことによって作られる腫瘍塊を作成した。そこで、XVIII型コラーゲンに特異的モノクローン抗体を担癌マウスに接種することにより、癌塊が増悪腫大するかどうかを観察することとした。その結果、この特異的モノクローン抗体はがん細胞をアポトーシスに導くことなく、肝癌の容積の増大を認めた。しかしながら、この特異抗体だけでは腫瘍細胞の増殖を促進することはなさそうであった。これらの結果は、エンドスタチンの抗腫瘍効果を支持する重要な所見であり、それだけでなく今回使用したものクローン抗体は、特異的にXVIII型コラーゲンに反応し、エンドスタチンの抗腫瘍効果を抑制することにまで至ったものであり、重要な知見であると思われる。

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  • 新規アグリカナーゼのリウマチ性関節炎における役割と診断的応用

    研究課題/領域番号:15390459  2003年 - 2004年

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    廣畑 聡, 二宮 善文, 大橋 俊孝, 米澤 朋子, 西田 圭一郎

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    配分額:15000000円 ( 直接経費:15000000円 )

    1 新しく発見したアグリカナーゼ遺伝子の発現検討
    IL-1β刺激後した、培養軟骨肉腫細胞株・ヒト軟骨細胞・ヒト線維芽細胞よりそれぞれmRNAを抽出し、リアルタイムRT-PCRにて、各アグリカナーゼの発現を定量的に比較検討を行った。線維芽細胞におけるADAMTS-9の発現増加と比較して、軟骨肉腫細胞株および軟骨細胞におけるADAMTS-9の発現増加は大であり、この新規アグリカナーゼは関節においてサイトカイン刺激で大きく誘導される遺伝子であることが明らかとなった。さらに、TNF-αとIL-1βの同時刺激により、ADAMTS9は相乗的に発現が増加することも明らかとなった。ADAMTS-9のmRNA発現レベルは他のどのADAMTSよりも強力であった。
    2 アグリカナーゼに対する特異的抗体
    ADAMTS-9に対するポリクローナル抗体を作成し、ウエスタンブロット法にて予想通りのサイズのバンドが得られた。IL-1β刺激後一過性にADAMTS-9タンパクが発現することが確認された。本抗体はWestern blotで利用可能であるが、免疫染色にはアフィニティカラムによる更なる精製などが必要と結論された。
    3 アグリカナーゼノックアウトマウスの作製
    海外共同研究にてES細胞への組み込みが終了しヘテロマウスの段階となった。
    4 アグリカナーゼの誘導機構の解明
    MAP kinase情報伝達経路の阻害剤(PD98059,SB203580)を添加し、IL-1β刺激による同経路のリン酸化がADAMTS-9の誘導にどう関与しているかを明らかにした。

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  • 心筋梗塞治癒機転への新規マトリックスメタロプロテアーゼ―ADAMTS―の関与

    研究課題/領域番号:14657171  2002年 - 2003年

    日本学術振興会  科学研究費助成事業 萌芽研究  萌芽研究

    草地 省蔵, 二宮 善文, 廣畑 聡, 村上 充

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    配分額:3500000円 ( 直接経費:3500000円 )

    ADAMTS-1(A Disintegrin And Metalloprotease with ThromboSpondin motifs-1)は約5年程前に発見された新しい細胞外マトリックス(ECM)分解酵素群の中の一構成メンバーである。急性心筋梗塞後の左室リモデリングには、マトリックスメタロプロテアーゼ(MMP)をはじめとするECM分解酵素の重要性が最近認識されている。
    予備実験としてADAMTS-1の心筋梗塞における発現動態をノーザンブロット法にて検討したところ、梗塞急性期に非常に強い発現がみられADAMTS-1は従来のMMPとは異なった役割を持つ可能性が示唆された。
    1 ADAMTS-1に影響を与える薬剤の検討
    ラット実験的心筋梗塞モデルにアンジオテンシン変換酵素阻害剤を投与し、ADAMTS1発現へ与える影響を検討した。コントロールとして、コラーゲンを用いて、比較検討したが、ADAMTS1の発現量には有意な変化は認められなかった。また、我々の梗塞モデルでは、梗塞後比較的早期の段階では、コラーゲンがむしろ上昇する傾向にあった。このことはこれまでの報告では見られない変化であり、我々の梗塞モデルにのみ見られる現象なのか、または解析方法に問題があるために見られた変化なのか解決することはできなかった。
    2 ノックアウトマウスを用いた検討
    ノックアウトマウスを作製し、維持管理している金沢大学がん研究所久野耕嗣博士と連絡を取ったが、残念ながら共同研究の実施にまでは至らなかった。RNA干渉法など他の方法を用いての解析が有効と考えられた。
    これらの研究成果は、日本循環器学会学術集会などにおいて発表し、報告した。

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  • 血液脳関門における血管内皮細胞下基底膜の役割

    研究課題/領域番号:14370434  2002年 - 2003年

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    二宮 善文, 廣畑 聡, 大橋 俊孝, 米澤 朋子, 大塚 愛二

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    配分額:14100000円 ( 直接経費:14100000円 )

    この2年間で私どもは、血液脳関門に関係すると思われる新規遺伝子リミトリンを同定し、これが血液脳関門と関係することを支持する結果を得た。私どもは、脳毛細血管系より脳以外血管系を引き算するという方法でcDNAsを単離し、ノーザンブロット法、シーケンス検索、等により脳毛細血管系に特異的cDNAsを選出した。さらに、数種類のクローンにつきアミノ酸配列を基に抗ペプチド抗体を作成し、その分布を調べると、ある抗体はマウス脳においてグリア境界膜に特異的に染まった。マウス脳の血管周囲グリア境界膜と脳表面グリア境界膜の両方のグリア境界膜に特異的に染まったため、私どもはこのcDNAが由来するタンパク質を、リミトリンと名付けた。このリミトリンは、膜貫通ドメインを有し、更にインムノグロブリンドメインを二つ持つため、インムノグロブリンスーパーファミリーに属することがわかった。In vivoでアストロサイトが産生することが予想され、免疫電子顕微鏡的観察によって、そのことが確認された。さらに、培養アストロサイトが大量にリミトリンを産生することも確認できた。生体脳では、血液脳関門が機能するのは脳実質内の毛細血管であるが、総ての毛細血管周囲で機能している訳ではなく、脳実質内の、いくつかの場所においては血液脳関門が機能していない場所がある。私どもはこれらの正中隆起やsubfornical organ等の場所においてリミトリンが発現しているかどうかを調べると、陰性であった。さらに、マウス脳実質損傷を作成し、その治癒過程でのリミトリン遺伝子の発現を観察すると、まず脳実質の損傷とともにリミトリンは発現停止し、その治癒過程では、損傷部位周辺の毛細血管新生とともにリミトリンが発現してくることを検知した。この現象は、リミトリンは血液脳関門の生理機能と直接関わっている可能性があるということが推測された。

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  • がん特異的遺伝子導入法を用いた血管新生阻害治療の試み

    研究課題/領域番号:14030056  2002年

    日本学術振興会  科学研究費助成事業 特定領域研究  特定領域研究

    廣畑 聡, 大橋 俊孝

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    配分額:6400000円 ( 直接経費:6400000円 )

    本研究の目的は、がん休眠療法の遺伝子治療の開発である。IV型コラーゲンα3鎖のNC1ドメインは、tumstatinとも呼ばれ、血管新生阻害作用を持つことが報告されている。しかしながらIV型コラーゲンα3鎖のNC1ドメインを治療に利用するにあたっては、同部位がGoodpasture症候群の自己抗原認識部位であることから、がん特異的な遺伝子発現が重要と考えられた。
    そこでhTERT(ヒトテロメラーゼ遺伝子)のプロモーター領域を組み込んだベクターにIV型コラーゲンα3鎖のNC1ドメインを下流に位置することにより、がん細胞特異的遺伝子導入法を試みた。コントロールとして、LacZをいれたベクターによる検討では、hTERTの発現がない細胞である正常内皮細胞には、観察しえた限りではX-gal染色は見られなかった。内皮細胞の他に心臓由来線維芽細胞を用いた実験でも同様の結果が得られた。がん細胞(PC-3,DU145)においてのみ、LacZの発現が見られた。この結果は、CMVベクター下にLacZを挿入した(細胞特異性がない)ものを用いたものと比較して著しい差は認められなかった。
    NC1ドメインの遺伝子発現効率は、LacZ細胞とほぼ同等であると考えられたが、タンパクレベルの発現は充分なものではなかった。血管新生阻害効果を治療応用するには、発現効率を高めることが必須であり、アデノウイルスを用いた新しい発現カセットを作成が重要と考えられた。

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  • ADAMTSによるアミロイド前駆体蛋白のプロセッシングと細胞外基質への影響

    研究課題/領域番号:13877097  2001年 - 2002年

    日本学術振興会  科学研究費助成事業 萌芽研究  萌芽研究

    廣畑 聡, 米澤 朋子, 大橋 俊孝, 二宮 善文, 百田 龍輔

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    配分額:2000000円 ( 直接経費:2000000円 )

    ADAMファミリーのうち、ADM-10とADAM-17はαセクレターゼ機能を持つことが知られているが、ADAMTSが同様な機能を持つか検討した。
    まず、基礎的実験としてADAMTS-1はその遺伝子発現がリポポリサッカライド刺激により、各臓器において発現が上昇することから炎症において何らかの役割を持つことが示唆されている。そこで、ラット実験的心筋梗塞モデルを用いてADAMTS-1の発現形式をノーザンブロット法にて検討した。ADAMTS-1は非梗塞心臓では弱い発現しか認めなかったが、梗塞心においては、梗塞後6時間でその発現が大きく上昇していた。
    マウス脳におけるADAMTSの発現をADAMTS-1〜7において検討したが、いずれもそれほど強くなかった。海外共同研究として、アミロイド前駆体蛋白を強制発現し、恒常的に発現する細胞株を樹立している、アラバマ大学Fukuchi教授らと共同実験を開始した。同細胞株は、通常の神経系細胞よりも過剰にアミロイド前駆体蛋白を発現している。これまでの検討によって過剰なアミロイド蛋白前駆体が細胞表面及び培養上清中に存在することが確認された。この実験系において過剰なアミロイド前駆体の切断がαセクレターゼによって制御されているかどうかを検討する目的でこの細胞系におけるαセクレターゼ発現の検討を開始した。実験の条件検討が複雑であり、切断の確認は困難であった。今後は、In vivoの系における実験系の確立およびアルツハイマー脳におけるADAMTSの発現解析が重要と考えられた。

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  • 新アグリカナーゼの同定と特異的抗体・ノックアウトマウス作製-リウマチ性関節炎の早期診断へ-

    研究課題/領域番号:13470312  2001年 - 2002年

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    廣畑 聡, 米澤 朋子, 大橋 俊孝, 二宮 善文, 百田 龍輔

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    配分額:14000000円 ( 直接経費:14000000円 )

    1.リアルタイムPCR法によるADAMTS遺伝子の発現
    岡山大学にて樹立されたヒト軟骨肉腫由来細胞株(OUMS-27)をインターロイキン(IL)-1β刺激下に培養し、ADAMTS遺伝子の発現を検討した。刺激後、6,12,24,48時間と経時的に細胞からmRNAを抽出し、リアルタイムRT-PCRを行い、各ADAMTSの発現を定量的に比較した。内部標準コントロールとしてGAPDHを用いた。ADAMTS-1,2,3,4,5,6,7,8,9のプライマー設計及びリアルタイムPCRの条件設定を行った。アグリカナーゼとしては、ADAMTS-1,4,5が報告されているが、ADAMTS-1,4,5それぞれのOUMS-27細胞におけるIL-1βに対する反応は異なっていた。
    また、細胞内情報伝達系の解析を行ったところ、MAPK-JNK pathwayが関与していることが明らかとなった。
    2.特異的抗体の作製
    ADAMTS-1に対する特異的抗体を2種類作成した。ADAMTS-1の2箇所のペプチドを抗原として家兎に免疫し、抗体を得た。特異性の評価は、IL-1β刺激していない培養OUMS-27細胞からタンパクを抽出し、ウエスタンブロッティングで行ったところ、約100kDaと70kDaのところに各一本ずつ明瞭なバンドを認めた。既報の通り、自己プロセッシングを受けているものと推察された。
    3.ノックアウトマウス
    海外共同研究者との間で、ノックアウトマウス作製を計画し、ES細胞への組み込みが完了した。

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